EP1087961B1 - Phenoxylpropanolamines, method for the production thereof and pharmaceutical compositions containing the same - Google Patents

Phenoxylpropanolamines, method for the production thereof and pharmaceutical compositions containing the same Download PDF

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EP1087961B1
EP1087961B1 EP99923710A EP99923710A EP1087961B1 EP 1087961 B1 EP1087961 B1 EP 1087961B1 EP 99923710 A EP99923710 A EP 99923710A EP 99923710 A EP99923710 A EP 99923710A EP 1087961 B1 EP1087961 B1 EP 1087961B1
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alk
group
product
formula
mole
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French (fr)
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EP1087961A1 (en
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Roberto Cecchi
Tiziano Croci
Umberto Guzzi
Eric Marsault
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Sanofi Aventis France
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Sanofi Synthelabo SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
    • C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
    • C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
    • C07D303/22—Ethers with hydroxy compounds containing no oxirane rings with monohydroxy compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/04—Drugs for genital or sexual disorders; Contraceptives for inducing labour or abortion; Uterotonics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/06—Antiabortive agents; Labour repressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/40—Radicals substituted by oxygen atoms
    • C07D307/42—Singly bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the present invention relates to new phenoxypropanolamines, pharmaceutical compositions containing them, a process for their preparation and intermediaries in this process.
  • BE 902897 describes aryloxypropanolamines carrying a 4-piperidininyl-1-substituted group on the amine, these compounds having a ⁇ 1 -blocking and ⁇ -blocking activity.
  • J. Org. Chem., 1998, 63 : 889: 894 describes other aryloxypropanolamines carrying a 4-piperidinyl-1-substituted group on the amine.
  • phenoxypropanolamines carrying a 1- (pyrid-2-yl) -piperidin-4-yl radical on the amine have an agonist activity with respect to ⁇ 3 -adrenergic receptors.
  • (C 1 -C 4 ) Alk denotes a monovalent radical of a C 1 -C 4 hydrocarbon saturated with a straight or branched chain.
  • the salts of the compounds of formula (I) and (Ia) according to the present invention include addition salts with mineral or organic acids pharmaceutically acceptable such as the hydrochloride, the bromohydrate, the sulfate, hydrogen sulfate, dihydrogen phosphate, citrate, maleate, tartrate, fumarate, gluconate, methanesulfonate, 2-naphthalenesulfonate, etc., as the salts addition which allow proper separation or crystallization of the compounds of formula (I) or (Ia) such as picrate, oxalate or addition salts with acids optically active, for example camphorsulfonic acids and acids mandelics or substituted mandelics.
  • mineral or organic acids pharmaceutically acceptable such as the hydrochloride, the bromohydrate, the sulfate, hydrogen sulfate, dihydrogen phosphate, citrate, maleate, tartrate, fumarate, gluconate, methanesulfonate, 2-naphthal
  • the salts also include the salts with mineral bases, preferably those with alkali metals such as sodium or potassium, or with bases organic.
  • optically pure stereoisomers as well as the mixtures of isomers of the compounds of formula (I) and (Ia), due to asymmetric carbons or to the sulfinyl group in the meaning of R 1a or R 1 , in any proportion, are part of the present invention.
  • Preferred compounds of the present invention include the compounds of formula (I) or (Ia) where the group R 2 is in the 5 position of pyridine.
  • R 2 is chosen from -COOH, -COO (C 1 -C 4 ) Alk, -CN, -NO 2 , -CONR 3 R 4 , - NHSO 2 - (C 1 -C 4 ) Alk.
  • R 2 is a halogen, in particular chlorine.
  • Still other preferred compounds are those where n and m are zero.
  • the compounds of formula (I) or (Ia) can be prepared by treating a compound of formula (II): in which R 1 b is R 1a or R 1 as indicated above, P 'is a protective group and X is a group of formula (a) or (b) where Gp is a leaving group such as tosylate, mesylate or a halogen, with an amine of formula (III) where n, m and R 2 are as defined above, by cleaving the group P 'according to the usual methods and optionally transforming the compound of formula (I) or (Ia) thus obtained into one of its salts.
  • reaction between the compounds of formula (II) and (III) is produced in an organic solvent, such as a lower alcohol such as methanol, ethanol and isopropanol; dimethyl sulfoxide; a linear or cyclic ether; a friend of such as dimethylformamide or dimethylacetamide; using quantities at less equimolecular reagents, possibly in small excess of amine.
  • organic solvent such as a lower alcohol such as methanol, ethanol and isopropanol
  • dimethyl sulfoxide such as methanol, ethanol and isopropanol
  • dimethyl sulfoxide such as a linear or cyclic ether
  • a friend of such as dimethylformamide or dimethylacetamide such as dimethylformamide or dimethylacetamide
  • the reaction temperature is between room temperature and reflux temperature of the chosen solvent.
  • protecting groups P ′ the usual protecting groups can be used for hydroxy groups such as for example methoxyethoxymethyl (MEM) or benzyl.
  • MEM methoxyethoxymethyl
  • cleavage of these protective groups is carried out according to the usual methods for the chosen protecting group; in the case of the benzyl group for example by hydrogenation in the presence of a catalyst such as Pd / C in a suitable solvent; in the case of methoxyethoxymethyl (MEM) one can on the other hand use an acid such than trifluoroacetic acid.
  • the amines of formula (III) can be prepared by reaction of the suitable pyridines of formula (IV) where Hal represents a halogen and R 2 and m are as defined above, with a piperidine of formula (V) below where n is as defined above and P represents a protective group, in an organic solvent in the presence of a base, followed by cleavage of the P group of the compounds of formula (VI) thus obtained.
  • reaction solvent it is possible to use, for example, dimethylformamide, pyridine, dimethyl sulfoxide, a linear or cyclic ether or a chlorinated solvent such as dichloromethane.
  • an alkali hydroxide for example, an alkali hydroxide, a carbonate alkaline such as potassium carbonate or a tertiary amine such as triethylamine.
  • the reaction temperature is between room temperature and reflux temperature of the chosen solvent.
  • protecting groups P it is possible to use the usual protecting groups for amines such as for example tert -butoxycarbonyl, acetyl, carbobenzyloxy.
  • cleavage of these protective groups is carried out according to the usual methods described the protective group chosen; in the case of tert -butoxycarbonyl for example, the cleavage is normally carried out by acid hydrolysis.
  • Particularly preferred compounds of formula (VII) are those where R 2 ° is chosen from the groups -COOH, -COO (C 1 -C 4 ) Alk, -CN, NO 2 , -CONR 3 ° R 4 °, -SO 2 NH 2 . and -NHSO 2 (C 1 -C 4 ) Alk.
  • the compounds of formula (I) and (Ia) are not very toxic; in particular, their acute toxicity is compatible with their use as medicaments for the treatment of diseases in which the compounds having an affinity for the ⁇ 3 receptor find their application.
  • the compounds of formula (I) and (Ia), as well as their pharmaceutically acceptable salts, can therefore be indicated for example in the treatment of gastrointestinal diseases such as irritable bowel syndrome, as modulators of intestinal motility, as lipolytics , anti-obesity, anti-diabetic, psychotropic, anti-glaucomatous, healing, anti-depressants, as an inhibitor of uterine contractions, as tocolytics to prevent or delay early delivery, for the treatment and / or prophylaxis of dysmenorrhea.
  • the compounds of formula (I) and (Ia) above and their salts and solvates pharmaceutically acceptable can be used in daily doses of 0.01 to 20 mg per kilogram of body weight of the mammal to be treated, preferably in doses 0.1 to 10 mg / kg daily.
  • the dose may preferably vary from 0.5 mg to 1500 mg per day, especially 2.5 to 500 mg depending on the age of the subject to be treated, the type of treatment, prophylactic or curative, and the severity of the condition.
  • Compounds of formula (I) and (Ia) are generally administered in dosage units of 0.1 to 500 mg, preferably from 0.5 to 100 mg of active principle, one to five times a day.
  • Said dosage units are preferably formulated in compositions pharmaceuticals in which the active ingredient is mixed with an excipient pharmaceutical.
  • the present invention relates to pharmaceutical compositions containing, as active ingredient, a compound of formula (I) or (Ia) above or one of its salts and solvates pharmaceutically acceptable.
  • compositions of the present invention for administration oral, sublingual, subcutaneous, intramuscular, intravenous, topical, transdermal or rectal, the active ingredients of formula (I) or (Ia) above, their salts and pharmaceutically acceptable solvates can be administered in forms administration units, mixed with conventional pharmaceutical carriers, animals and humans for the treatment of the above conditions.
  • Shapes appropriate administration units include oral forms such as tablets, capsules, powders, granules and solutions or suspensions oral, sublingual and oral forms of administration, forms of administration subcutaneous, intramuscular or intravenous, local administration forms and forms of rectal administration.
  • a solid composition in the form of tablets When preparing a solid composition in the form of tablets, it is mixed the main active ingredient with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like.
  • a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like.
  • sucrose or other suitable materials we can coat the tablets with sucrose or other suitable materials or you can treat them so that they have prolonged or delayed activity and they release continuously a predetermined amount of active ingredient.
  • a preparation in capsules is obtained by mixing the active ingredient with a diluting and pouring the mixture obtained into soft or hard capsules.
  • a preparation in the form of syrup or elixir may contain the active ingredient together with a sweetener, preferably calorie-free, methylparaben and propylparaben as antiseptics, as well as a flavoring agent and a color appropriate.
  • a sweetener preferably calorie-free, methylparaben and propylparaben as antiseptics, as well as a flavoring agent and a color appropriate.
  • Water dispersible powders or granules may contain the ingredient active in admixture with dispersing agents or wetting agents, or agents suspension, such as polyvinylpyrrolidone, as well as with sweeteners or flavor correctors.
  • the active ingredient is mixed in an excipient for the preparation of creams or ointments or it is dissolved in a vehicle for intraocular administration, for example in the form of eye drops.
  • Suppositories are used for rectal administration. with binders that melt at the rectal temperature, for example cocoa butter or polyethylene glycols.
  • aqueous suspensions, saline or sterile and injectable solutions that contain dispersion and / or pharmacologically compatible wetting agents, for example propylene glycol or butylene glycol.
  • the active principle can also be formulated in the form of microcapsules, possibly with one or more supports or additives.
  • the present invention relates to a method of treatment of pathologies which are improved by a ⁇ 3 -agonist action, which comprises administering a compound of formula (I) or (Ia) or one of its salts or pharmaceutically acceptable solvates.
  • the compounds of formula (I) and (Ia), in particular the compounds (I) and (Ia) marked with an isotope, can also be used as laboratory tools in biochemical tests.
  • the compounds of formula (I) and (Ia) bind to the ⁇ 3 -adrenergic receptor.
  • Another specific object of the present invention is therefore a reagent which can be used in biochemical tests, which comprises at least one compound of formula (I) or (Ia) suitably marked.
  • Example 2 By operating as described in Example 2 but using the product of Example 3 instead of the product of Example 1, the title compound is obtained. Mp 148-150 ° C.
  • Example 2 By operating as described in Example 2 but using the product of Example 7 instead of the product of Example 1, and treating the hydrochloride salt thus obtained with an aqueous solution of NH 4 OH, the compound is obtained of the title. Mp 68-72 ° C.
  • Example 9 By operating as described in Example 9 but using the product of Example 8 instead of the product of Example 2, the title compound is obtained. Mp 160-162 ° C.
  • Example 9 By operating as described in Example 9 but using the product of Example 14 (base), instead of the product of Example 2, the title compound is obtained. Mp 115-117 ° C.
  • Example 16 By operating as described in Example 2 but using the product of Example 16 instead of the product of Example 1, the title compound is obtained. Mp 270-273 ° C.
  • Example 9 By operating as described in Example 9 but using the product of Example 17 base instead of the product of Example 2, the title compound is obtained. Mp : 190-192 ° C.
  • Example 9 By operating as described in Example 9 but using the product of Example 20 (base) instead of the product of Example 2, the title compound is obtained based.
  • the hydrochloride is prepared using a hydrochloric acid solution in isopropanol.
  • the title compound is obtained. Mp 195 ° C Dec.
  • Example 9 By operating as described in Example 9 but using the product of Example 23 bases instead of the product of Example 2 and absolute ethanol instead of dimethylsulfoxide, the base title compound is obtained.
  • the hydrochloride using of a hydrochloric acid solution in isopropanol.
  • the title compound is obtained. P.f .: 137-139.
  • the product from the previous step is heated for 7 hours at 55 ° C in 20 ml of CF 3 COOH.
  • the solvent is partially evaporated, ethyl acetate and toluene are added and the solvent is further evaporated.
  • Water saturated with Na 2 CO 3 is added and the mixture is extracted with ethyl acetate.
  • the crude reaction product is dried and purified by flash chromatography, eluting with a mixture of CH 2 Cl 2 , CH 3 OH, NH 4 OH, in variable proportions between 92: 8: 0.8 and 90:10: 1.
  • the title compound is obtained as a free base (mp: 95-100 ° C).
  • the product is dissolved in acetone and an HCl solution isopropanol is added, filtered and washed with acetone.
  • the title product is obtained. Mp: 173-175 ° C.
  • Example 27 in 18 ml of ethyl acetate and 18 ml of HCl in ethyl acetate (approximately 3N). It is filtered and washed with acetone. It is crystallized from isopropanol and the composed of the title. M.p .: 281-283 ° C.
  • Example 30 The product of Example 30 is heated for 3 hours at 40 ° C in a CH 2 Cl 2 solution containing 11 ml of CF 3 COOH. The solvent is evaporated and crystallized from acetone. The title product is obtained. Mp: 173 ° -175 ° C.
  • Example 12 The procedure is as described in Example 12 but using the product of Example 31 instead of the product of Example 6, the title product is obtained. Mp : 141-143 ° C.
  • Example 38a The product obtained in Example 38a) is treated with 100 ml of CF 3 COOH at 55 ° C for 6 hours. The solvent is evaporated off and water saturated with Na 2 CO 3 and ice are added.
  • Example 48 The product of Example 48 is reacted with the product of Example 4 (base), according to the process described in Example 9a.
  • the product resulting from this reaction is treated with CF 3 COOH at 55 ° C for 4 hours.
  • the product is crystallized from isopropanol. Mp: 123-126 ° C
  • Example 51a The product of Example 51a is hydrogenated according to the process described in Example 9b, operating at a pressure that varies between ambient pressure and 50 psi.
  • a solution containing 1.17 g (0.0063) is heated at 80 ° C. for 24 hours. mole) of the product of Example 55, 1.27 g (0.0063 mole) of the product of preparation 1, 0.9 ml of triethylamine and NaI in 34.2 ml of dimethylformamide.
  • Example 57 base 0.292 g (0.00114 mole) of 4-benzyloxy-1- (2,3-epoxypropoxy) benzene in 15 ml of ethanol. It is evaporated under reduced pressure and purifies the reaction crude by chromatography, eluting with a mixture CH3OH / ethyl acetate 9/1.
  • Example 38b The procedure is as described in Example 38b) but using the product of Example 59a) instead of the product of Example 38a).
  • the title product is obtained.
  • Example 64a 0.22 g (0.0007 mole) of the product is heated at reflux overnight.
  • Mp 124-126 ° C
  • Example 64a The product of Example 64a is hydrogenated according to the process described in the example. 9b. The title product is obtained. Mp : 103-105 ° C.
  • Example 50 The product of Example 50 is reacted with 4-amino-1- (6-chloropyrid-2yl) -piperidine (prepared as described in EP 21973) according to the method described in Example 51.
  • Example 50 The product of Example 50 is reacted with the product of Example 57 (base) under the conditions described in Example 51. The title product is obtained.

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Abstract

The invention relates to compounds of formula (Ia), wherein R1a represents hydrogen, an -S(O)Z-(C1-C4)Alk group, a -CO(C1-C4)Alk group, an -NHSO2-(C1-C4)Alk, an NHCO(C1-C4)Alk group, a 2-furyl group or a halogen; R2 represents hydrogen or a (C1-C4)Alk group, a (C1-C4)oxalkylate group, a halogen, -COOH, -COO(C1-C4)Alk, -CN, -CONR3R4, -NO2, -SO2NH2, -NHSO2(C1-C4)Alk; m and n independently represent 0, 1 or 2; R3 and R4 represent independently hydrogen or a (C1-C4)Alk group; Z is 1 or 2. The invention also relates to the salts or solvates, pharmaceutical compositions containing said compounds, a method for the preparation thereof and to synthesis intermediates.

Description

La présente invention concerne de nouvelles phénoxypropanolamines, les compositions pharmaceutiques les contenant, un procédé pour leur préparation et des intermédiaires dans ce procédé.The present invention relates to new phenoxypropanolamines, pharmaceutical compositions containing them, a process for their preparation and intermediaries in this process.

BE 902897 décrit des aryloxypropanolamines portant un groupe 4-pipéridininyl-1-substitué sur l'amine, ces composés ayant une activité β1-bloquante et α-bloquante. J. Org. Chem., 1998, 63:889:894, décrit d'autres aryloxypropanolamines portant un groupe 4- pipéridinyl-1-substitué sur l'aminé.BE 902897 describes aryloxypropanolamines carrying a 4-piperidininyl-1-substituted group on the amine, these compounds having a β 1 -blocking and α-blocking activity. J. Org. Chem., 1998, 63 : 889: 894, describes other aryloxypropanolamines carrying a 4-piperidinyl-1-substituted group on the amine.

Il a été maintenant trouvé que des phénoxypropanolamines portant un radical 1-(pyrid-2-yl)-pipéridin-4-yl sur l'amine possèdent une activité agoniste vis-à-vis des récepteurs β3-adrénergiques.It has now been found that phenoxypropanolamines carrying a 1- (pyrid-2-yl) -piperidin-4-yl radical on the amine have an agonist activity with respect to β 3 -adrenergic receptors.

Ainsi, la présente invention concerne, selon un de ses aspects, des phénoxypropanolamines de formule (Ia)

Figure 00010001

  • R1a représente l'hydrogène, un groupe -S(O)z-(C1-C4)Alk, un groupe -CO(C1-C4)Alk, un groupe -NHSO2-(C1-C4)Alk, un groupe NHCO(C1-C4)Alk, un groupe 2-furyle ou un halogène;
  • R2 représente l'hydrogène ou un groupe (C1-C4)Alk, un groupe (C1-C4)alcoxyle, un halogène, -COOH, -COO(C1-C4)Alk, -CN, -CONR3R4, -NO2, -SO2NH2, -NHSO2(C1-C4)Alk;
    m et n indépendamment 0, 1 ou 2;
  • R3 et R4 représentent indépendamment l'hydrogène ou un groupe (C1-C4)Alk;
    Z est 1 ou 2;
    •    et leurs sels ou solvates.Thus, the present invention relates, according to one of its aspects, to phenoxypropanolamines of formula (Ia)
    Figure 00010001
  • R 1a represents hydrogen, a group -S (O) z - (C 1 -C 4 ) Alk, a group -CO (C 1 -C 4 ) Alk, a group -NHSO 2 - (C 1 -C 4 ) Alk, an NHCO group (C 1 -C 4 ) Alk, a 2-furyl group or a halogen;
  • R 2 represents hydrogen or a (C 1 -C 4 ) Alk group, a (C 1 -C 4 ) alkoxyl group, a halogen, -COOH, -COO (C 1 -C 4 ) Alk, -CN, - CONR 3 R 4 , -NO 2 , -SO 2 NH 2 , -NHSO 2 (C 1 -C 4 ) Alk;
    m and n independently 0, 1 or 2;
  • R 3 and R 4 independently represent hydrogen or a (C 1 -C 4 ) Alk group;
    Z is 1 or 2;
    • and their salts or solvates.

    Selon un autre de ses aspects, l'invention concerne des composés de formule (I):

    Figure 00020001
    où

  • R1 représente l'hydrogène, un groupe -S(O)z-(C1-C4)Alk, un groupe -CO(C1-C4)Alk ou un groupe -NHSO2-(C1-C4)Alk;
  • R2 représente l'hydrogène ou un groupe (C1-C4)Alk, un groupe (C1-C4)alcoxyle, un halogène, -COOH, -COO(C1-C4)Alk, -CN, -CONR3R4, -NO2, -SO2NH2, -NHSO2(C1-C4)Alk;
    m et n indépendamment 0, 1 ou 2;
  • R3 et R4 représentent indépendamment l'hydrogène ou un groupe (C1-C4)Alk;
  • Z est 1 ou 2;
    • et leurs sels ou solvates.According to another of its aspects, the invention relates to compounds of formula (I):
    Figure 00020001
    or
  • R 1 represents hydrogen, a group -S (O) z - (C 1 -C 4 ) Alk, a group -CO (C 1 -C 4 ) Alk or a group -NHSO 2 - (C 1 -C 4 ) Alk;
  • R 2 represents hydrogen or a (C 1 -C 4 ) Alk group, a (C 1 -C 4 ) alkoxyl group, a halogen, -COOH, -COO (C 1 -C 4 ) Alk, -CN, - CONR 3 R 4 , -NO 2 , -SO 2 NH 2 , -NHSO 2 (C 1 -C 4 ) Alk;
    m and n independently 0, 1 or 2;
  • R 3 and R 4 independently represent hydrogen or a (C 1 -C 4 ) Alk group;
  • Z is 1 or 2;
    • and their salts or solvates.

    Dans la présente description le terme "(C1-C4)Alk" désigne un radical monovalent d'un hydrocarbure en C1-C4 saturé à chaíne droite ou ramifiée.In the present description the term "(C 1 -C 4 ) Alk" denotes a monovalent radical of a C 1 -C 4 hydrocarbon saturated with a straight or branched chain.

    Les sels des composés de formule (I) et (Ia) selon la présente invention comprennent aussi bien les sels d'addition avec des acides minéraux ou organiques pharmaceutiquement acceptables tels que le chlorhydrate, le bromohydrate, le sulfate, l'hydrogénosulfate, le dihydrogénophosphate, le citrate, le maléate, le tartrate, le fumarate, le gluconate, le méthanesulfonate, le 2-naphtalènesulfonate, etc., que les sels d'addition qui permettent une séparation ou une cristallisation convenable des composés de formule (I) ou (Ia) tels que le picrate, l'oxalate ou les sels d'addition avec des acides optiquement actifs, par exemple les acides camphorsulfoniques et les acides mandéliques ou mandéliques substitués.The salts of the compounds of formula (I) and (Ia) according to the present invention include addition salts with mineral or organic acids pharmaceutically acceptable such as the hydrochloride, the bromohydrate, the sulfate, hydrogen sulfate, dihydrogen phosphate, citrate, maleate, tartrate, fumarate, gluconate, methanesulfonate, 2-naphthalenesulfonate, etc., as the salts addition which allow proper separation or crystallization of the compounds of formula (I) or (Ia) such as picrate, oxalate or addition salts with acids optically active, for example camphorsulfonic acids and acids mandelics or substituted mandelics.

    De plus, lorsque les composés de formule (I) et (Ia) possèdent un groupe carboxy libre les sels comprennent aussi les sels avec des bases minérales, de préférence celles avec des métaux alcalins tels que le sodium ou le potassium, ou avec des bases organiques.In addition, when the compounds of formula (I) and (Ia) have a carboxy group the salts also include the salts with mineral bases, preferably those with alkali metals such as sodium or potassium, or with bases organic.

    Les stéréoisomères optiquement purs, ainsi que les mélanges d'isomères des composés de formule (I) et (Ia), dus aux carbones asymétriques ou au groupe sulfinyle dans la signification de R1a ou R1, dans une proportion quelconque, sont partie de la présente invention.The optically pure stereoisomers, as well as the mixtures of isomers of the compounds of formula (I) and (Ia), due to asymmetric carbons or to the sulfinyl group in the meaning of R 1a or R 1 , in any proportion, are part of the present invention.

    Des composés préférés de la présente invention comprennent les composés de formule (I) ou (Ia) où le groupe R2 est dans la position 5 de la pyridine. Preferred compounds of the present invention include the compounds of formula (I) or (Ia) where the group R 2 is in the 5 position of pyridine.

    D'autres composés préférés comprennent les composés de formule (I) ou (Ia) où le groupe R2 est dans la position 6 de la pyridine.Other preferred compounds include the compounds of formula (I) or (Ia) where the group R 2 is in position 6 of pyridine.

    D'autres composés préférés sont ceux où le groupe (C1-C4)Alk est un groupe méthyle ou éthyle.Other preferred compounds are those where the group (C 1 -C 4 ) Alk is a methyl or ethyl group.

    D'autres composés préférés sont ceux où R2 est choisi parmi -COOH, -COO(C1-C4)Alk, -CN, -NO2, -CONR3R4, - NHSO2-(C1-C4)Alk.Other preferred compounds are those where R 2 is chosen from -COOH, -COO (C 1 -C 4 ) Alk, -CN, -NO 2 , -CONR 3 R 4 , - NHSO 2 - (C 1 -C 4 ) Alk.

    D'autres composés préférés sont ceux où R2 est un halogène notamment le chlore.Other preferred compounds are those where R 2 is a halogen, in particular chlorine.

    D'autres composés préférés encore sont ceux où n et m sont zéro.Still other preferred compounds are those where n and m are zero.

    Les composés de formule (I) ou (Ia) peuvent être préparés en traitant un composé de formule (II) :

    Figure 00030001
    dans laquelle R1b est R1a ou R1 tels qu'indiqués ci-dessus, P' est un groupe protecteur et X est un groupe de formule (a) ou (b)
    Figure 00030002
    où Gp est un groupe partant tel que le tosylate, le mésylate ou un halogène, avec une amine de formule (III)
    Figure 00030003
    où n, m et R2 sont tels que définis ci-dessus, en clivant le groupe P' selon les méthodes usuelles et éventuellement transformant le composé de formule (I) ou (Ia) ainsi obtenu en un de ses sels.The compounds of formula (I) or (Ia) can be prepared by treating a compound of formula (II):
    Figure 00030001
    in which R 1 b is R 1a or R 1 as indicated above, P 'is a protective group and X is a group of formula (a) or (b)
    Figure 00030002
    where Gp is a leaving group such as tosylate, mesylate or a halogen, with an amine of formula (III)
    Figure 00030003
    where n, m and R 2 are as defined above, by cleaving the group P 'according to the usual methods and optionally transforming the compound of formula (I) or (Ia) thus obtained into one of its salts.

    Plus particulièrement, la réaction entre les composés de formule (II) et (III) est réalisée dans un solvant organique, tel qu'un alcool inférieur comme le méthanol, l'éthanol et l'isopropanol; le diméthylsulfoxyde; un éther linéaire ou cyclique; un amide comme le diméthylformamide ou le diméthylacétamide; en utilisant des quantités au moins équimoléculaires des réactifs, éventuellement en faible excès d'amine.More particularly, the reaction between the compounds of formula (II) and (III) is produced in an organic solvent, such as a lower alcohol such as methanol, ethanol and isopropanol; dimethyl sulfoxide; a linear or cyclic ether; a friend of such as dimethylformamide or dimethylacetamide; using quantities at less equimolecular reagents, possibly in small excess of amine.

    La température de la réaction est comprise entre la température ambiante et la température de reflux du solvant choisi. The reaction temperature is between room temperature and reflux temperature of the chosen solvent.

    Comme groupes protecteurs P', on peut utiliser les groupes protecteurs usuels pour les groupes hydroxy tels que par exemple le méthoxyéthoxyméthyle (MEM) ou le benzyle.As protecting groups P ′, the usual protecting groups can be used for hydroxy groups such as for example methoxyethoxymethyl (MEM) or benzyl.

    Le clivage de ces groupes protecteurs est effectué selon les méthodes habituelles pour le groupe protecteur choisi; dans le cas du groupe benzyle par exemple par hydrogénation en présence d'un catalyseur tel que le Pd/C dans un solvant convenable; dans le cas du méthoxyéthoxyméthyle (MEM) on peut par contre utiliser un acide tel que l'acide trifluoroacétique.The cleavage of these protective groups is carried out according to the usual methods for the chosen protecting group; in the case of the benzyl group for example by hydrogenation in the presence of a catalyst such as Pd / C in a suitable solvent; in the case of methoxyethoxymethyl (MEM) one can on the other hand use an acid such than trifluoroacetic acid.

    La plupart des époxydes de formule (II) sont des composés connus en littérature ou bien ils peuvent être préparés par des procédés analogues à ceux décrits dans la littérature.Most of the epoxides of formula (II) are compounds known in the literature or they can be prepared by methods analogous to those described in the literature.

    Certains époxydes de formule (II) sont par exemple décrits dans WO 96/04233 et dans US 4,396,629.Certain epoxides of formula (II) are for example described in WO 96/04233 and in US 4,396,629.

    Les isomères purs des composés de formule (II) où X est un groupe (a) et R1b représente le groupe SOCH3, résolus au carbone asymétrique, sont nouveaux, ayant été obtenus pour la prémière fois comme stéréoisomères purs dépourvus d'autres stéréroisomères et d'autres impuretés.The pure isomers of the compounds of formula (II) where X is a group (a) and R 1b represents the group SOCH 3 , resolved to asymmetric carbon, are new, having been obtained for the first time as pure stereoisomers without other steroisomers and other impurities.

    Certaines époxydes de formule (II) sont nouveaux et constituent un autre objet de la présente invention.Certain epoxides of formula (II) are new and constitute another object of the present invention.

    Plus particulièrement, il s'agit des composés de formule (II'):

    Figure 00040001
    dans laquelle P' est tel que défini dans la formule (II), X est un groupe (a) tel que défini ci-dessus et Y représente un atome de brome ou un groupe 2-furyle, leurs isomères optiquement actifs et leurs sels. Ils sont préparés comme décrits dans les exemples 44 et 47.More particularly, these are the compounds of formula (II ′):
    Figure 00040001
    wherein P 'is as defined in formula (II), X is a group (a) as defined above and Y represents a bromine atom or a 2-furyl group, their optically active isomers and their salts. They are prepared as described in Examples 44 and 47.

    Les amines de formule (III) peuvent être préparées par réaction des pyridines convenables de formule (IV)

    Figure 00040002
    où Hal représente un halogène et R2 et m sont tels que définis ci-dessus, avec une pipéridine de formule (V) ci-dessous
    Figure 00050001
    où n est tel que défini ci-dessus et P représente un groupe protecteur, dans un solvant organique en présence d'une base, suivie par clivage du groupe P des composés de formule (VI) ainsi obtenus.
    Figure 00050002
    The amines of formula (III) can be prepared by reaction of the suitable pyridines of formula (IV)
    Figure 00040002
    where Hal represents a halogen and R 2 and m are as defined above, with a piperidine of formula (V) below
    Figure 00050001
    where n is as defined above and P represents a protective group, in an organic solvent in the presence of a base, followed by cleavage of the P group of the compounds of formula (VI) thus obtained.
    Figure 00050002

    Comme solvant de réaction, on peut bien utiliser par exemple le diméthylformamide, la pyridine, le diméthylsulfoxyde, un éther linéaire ou cyclique ou un solvant chloruré tel que le dichlorométhane.As reaction solvent, it is possible to use, for example, dimethylformamide, pyridine, dimethyl sulfoxide, a linear or cyclic ether or a chlorinated solvent such as dichloromethane.

    Comme base on peut utiliser par exemple un hydroxyde alcalin, un carbonate alcalin tel que le carbonate de potassium ou une amine tertiaire telle que la triéthylamine.As a base, for example, an alkali hydroxide, a carbonate alkaline such as potassium carbonate or a tertiary amine such as triethylamine.

    La réaction de condensation ci-dessus est complétée en quelques heures, normalement en 2-12 heures.The above condensation reaction is completed in a few hours, normally in 2-12 hours.

    La température de réaction est comprise entre la température ambiante et la température de reflux du solvant choisi.The reaction temperature is between room temperature and reflux temperature of the chosen solvent.

    Comme groupes protecteurs P, on peut utiliser les groupes protecteurs usuels pour les amines tels que par exemple le tert-butoxycarbonyle, l'acétyle, le carbobenzyloxy.As protecting groups P, it is possible to use the usual protecting groups for amines such as for example tert -butoxycarbonyl, acetyl, carbobenzyloxy.

    Le clivage de ces groupes protecteurs est effectué selon les méthodes habituelles décrites le groupe protecteur choisi; dans le cas du tert-butoxycarbonyle par exemple, le clivage est normalement effectué par hydrolyse acide.The cleavage of these protective groups is carried out according to the usual methods described the protective group chosen; in the case of tert -butoxycarbonyl for example, the cleavage is normally carried out by acid hydrolysis.

    Certaines des amines intermédiaires de formule (III) et (VI), regroupées dans la formule (VII) ci-dessous

    Figure 00050003
    où

  • P° est l'hydrogène ou un groupe protecteur;
  • n° et m° sont 0, 1 ou 2;
  • R2° est un (C1-C4)Alk ; (C1-C4)alcoxyle, -COOH, -COO(C1-C4)Alk , -CN, - NO2, -CONR3°R4°, -SO2NH2, -NHSO2(C1-C4)Alk ;
  • R3° et R4° sont l'hydrogène ou un groupe (C1-C4)Alk;
    • à la condition que lorsque n° et m° sont zéro, R2° est autre que méthoxy dans la position 6 et qu'halogène dans la position 3 ou 6 de la pyridine; lorsque n° est 1 m° est 0, R2° est autre que chlore dans la position 6 de la pyridine et lorsque n° est 0 m° est 0 ou 1, R2° est autre que méthyle;
    ainsi que leurs sels, sont des composés nouveaux et constituent un objet ultérieur de la présente invention.Some of the intermediate amines of formula (III) and (VI), grouped in formula (VII) below
    Figure 00050003
    or
  • P ° is hydrogen or a protecting group;
  • n ° and m ° are 0, 1 or 2;
  • R 2 ° is a (C 1 -C 4 ) Alk; (C 1 -C 4 ) alkoxyl, -COOH, -COO (C 1 -C 4 ) Alk, -CN, - NO 2 , -CONR 3 ° R 4 °, -SO 2 NH 2 , -NHSO 2 (C 1 -C 4 ) Alk;
  • R 3 ° and R 4 ° are hydrogen or a (C 1 -C 4 ) Alk group;
    • provided that when n ° and m ° are zero, R 2 ° is other than methoxy in position 6 and that halogen in position 3 or 6 of pyridine; when n ° is 1 m ° is 0, R 2 ° is other than chlorine in position 6 of pyridine and when n ° is 0 m ° is 0 or 1, R 2 ° is other than methyl;
    as well as their salts, are new compounds and constitute a further object of the present invention.

    Des composés de formule (VII) particulièrement préférés sont ceux où R2° est choisi parmi les groupes -COOH, -COO(C1-C4)Alk, -CN, NO2, -CONR3°R4°, -SO2NH2. et
    -NHSO2(C1-C4)Alk.    Particularly preferred compounds of formula (VII) are those where R 2 ° is chosen from the groups -COOH, -COO (C 1 -C 4 ) Alk, -CN, NO 2 , -CONR 3 ° R 4 °, -SO 2 NH 2 . and
    -NHSO 2 (C 1 -C 4 ) Alk.

    D'autres composés de formule (VII) préférés sont ceux où R2° est dans la position 5 ou 6 de la pyridine.Other preferred compounds of formula (VII) are those where R 2 ° is in the 5 or 6 position of pyridine.

    D'autres composés de formule (VII) préférés sont ceux où n° et m° sont zéro.Other preferred compounds of formula (VII) are those where n ° and m ° are zero.

    D'autres composés de formule (VII) particulièrement préférés sont ceux où P° est l'hydrogène.Other particularly preferred compounds of formula (VII) are those where P ° is hydrogen.

    Les composés de formule (I) et (Ia) ont montré une affinité très puissante vis-à-vis des récepteurs β3.The compounds of formula (I) and (Ia) have shown a very powerful affinity with respect to the β 3 receptors.

    L'activité des composés de la présente invention vis-à-vis de l'activité β3 a été mise en évidence à l'aide d'essais in vitro sur le colon humain selon la méthode décrite dans EP-B-436435 et dans T. Croci et al, Br. J. Pharmacol., 1997, 122: 139P.The activity of the compounds of the present invention vis-à-vis the β 3 activity has been demonstrated using in vitro tests on the human colon according to the method described in EP-B-436435 and in T. Croci et al, Br. J. Pharmacol., 1997, 122 : 139P.

    Plus particulièrement, on a constaté que les composés de formule (I) et (Ia) sont beaucoup plus actifs sur le côlon isolé que sur l'oreillette et sur la trachée.More particularly, it has been found that the compounds of formula (I) and (Ia) are much more active on the isolated colon than on the atrium and on the trachea.

    Ces propriétés surprenantes des composés de formule (I) et (Ia) permettent d'envisager leur utilisation comme médicaments à action β3.These surprising properties of the compounds of formula (I) and (Ia) make it possible to envisage their use as drugs with a β 3 action.

    De plus, les composés de formule (I) et (Ia) sont peu toxiques; notamment, leur toxicité aigüe est compatible avec leur utilisation comme médicaments pour le traitement de maladies dans lesquelles les composés ayant une affinité pour le récepteur β3 trouvent leur application. Les composés de formule (I) et (Ia), ainsi que leurs sels pharmaceutiquement acceptables, peuvent donc être indiqués par exemple dans le traitement des maladies gastro-intestinales telles que le syndrôme du colon irritable, comme modulateurs de la motricité intestinale, comme lipolytiques, agents anti-obésité, anti-diabétiques, psychotropes, anti-glaucomateux, cicatrisants, anti-dépressants, comme inhibiteur des contractions utérines, comme tocolytiques pour prévenir ou retarder les accouchement précoces, pour le traitement et/ou la prophylaxie de la dysménorrhée.In addition, the compounds of formula (I) and (Ia) are not very toxic; in particular, their acute toxicity is compatible with their use as medicaments for the treatment of diseases in which the compounds having an affinity for the β 3 receptor find their application. The compounds of formula (I) and (Ia), as well as their pharmaceutically acceptable salts, can therefore be indicated for example in the treatment of gastrointestinal diseases such as irritable bowel syndrome, as modulators of intestinal motility, as lipolytics , anti-obesity, anti-diabetic, psychotropic, anti-glaucomatous, healing, anti-depressants, as an inhibitor of uterine contractions, as tocolytics to prevent or delay early delivery, for the treatment and / or prophylaxis of dysmenorrhea.

    L'utilisation des composés de formule (I) et (Ia) ci dessus, ainsi que celle de leurs sels et solvates pharmaceutiquement acceptables pour la préparation de médicaments ci-dessus, constitue un aspect ultérieur de la présente invention. The use of the compounds of formula (I) and (Ia) above, as well as that of their pharmaceutically acceptable salts and solvates for the preparation of the above medicaments, constitutes a further aspect of the present invention.

    Pour une telle utilisation, on administre aux mammifères qui nécessitent un tel traitement une quantité efficace d'un composé de formule (I) ou (Ia) ou d'un de ses sels et solvates pharmaceutiquement acceptables.For such use, it is administered to mammals which require such a treatment an effective amount of a compound of formula (I) or (Ia) or of a salt thereof and pharmaceutically acceptable solvates.

    Les composés de formule (I) et (Ia) ci-dessus et leurs sels et solvates pharmaceutiquement acceptables peuvent être utilisés à des doses journalières de 0,01 à 20 mg par kilo de poids corporel du mammifère à traiter, de préférence à des doses journalières de 0,1 à 10 mg/kg. Chez l'être humain, la dose peut varier de préférence de 0,5 mg à 1500 mg par jour, notamment de 2,5 à 500 mg selon l'âge du sujet à traiter, le type de traitement, prophylactique ou curatif, et la gravité de l'affection. Les composés de formule (I) et (Ia) sont généralement administrés en unité de dosage de 0,1 à 500 mg, de préférence de 0,5 à 100 mg de principe actif, une à cinq fois par jour.The compounds of formula (I) and (Ia) above and their salts and solvates pharmaceutically acceptable can be used in daily doses of 0.01 to 20 mg per kilogram of body weight of the mammal to be treated, preferably in doses 0.1 to 10 mg / kg daily. In humans, the dose may preferably vary from 0.5 mg to 1500 mg per day, especially 2.5 to 500 mg depending on the age of the subject to be treated, the type of treatment, prophylactic or curative, and the severity of the condition. Compounds of formula (I) and (Ia) are generally administered in dosage units of 0.1 to 500 mg, preferably from 0.5 to 100 mg of active principle, one to five times a day.

    Lesdites unités de dosage sont de préférence formulées dans des compositions pharmaceutiques dans lesquelles le principe actif est mélangé avec un excipient pharmaceutique.Said dosage units are preferably formulated in compositions pharmaceuticals in which the active ingredient is mixed with an excipient pharmaceutical.

    Ainsi, selon un autre de ses aspects, la présente invention concerne des compositions pharmaceutiques renfermant, en tant que principe actif, un composé de formule (I) ou (Ia) ci-dessus ou un de ses sels et solvates pharmaceutiquement acceptables.Thus, according to another of its aspects, the present invention relates to pharmaceutical compositions containing, as active ingredient, a compound of formula (I) or (Ia) above or one of its salts and solvates pharmaceutically acceptable.

    Dans les compositions pharmaceutiques de la présente invention pour l'administration orale, sublinguale, sous-cutanée, intramusculaire, intraveineuse, topique, transdermique ou rectale, les ingrédients actifs de formule (I) ou (Ia) ci-dessus, leurs sels et solvates pharmaceutiquement acceptables peuvent être administrés sous formes unitaires d'administration, en mélange avec des supports pharmaceutiques classiques, aux animaux et aux êtres humains, pour le traitement des affections susdites. Les formes unitaires d'administration appropriées comprennent les formes par voie orale telles que les comprimés, les gélules, les poudres, les granulés et les solutions ou suspensions orales, les formes d'administration sublinguale et buccale, les formes d'administration sous-cutanée, intramusculaire ou intraveineuse, les formes d'administration locale et les formes d'administration rectale.In the pharmaceutical compositions of the present invention for administration oral, sublingual, subcutaneous, intramuscular, intravenous, topical, transdermal or rectal, the active ingredients of formula (I) or (Ia) above, their salts and pharmaceutically acceptable solvates can be administered in forms administration units, mixed with conventional pharmaceutical carriers, animals and humans for the treatment of the above conditions. Shapes appropriate administration units include oral forms such as tablets, capsules, powders, granules and solutions or suspensions oral, sublingual and oral forms of administration, forms of administration subcutaneous, intramuscular or intravenous, local administration forms and forms of rectal administration.

    Lorsqu'on prépare une composition solide sous forme de comprimés, on mélange l'ingrédient actif principal avec un véhicule pharmaceutique tel que la gélatine, l'amidon, le lactose, le stéarate de magnésium, le talc, la gomme arabique ou analogues. On peut enrober les comprimés de saccharose ou d'autres matières appropriées ou encore on peut les traiter de telle sorte qu'ils aient une activité prolongée ou retardée et qu'ils libèrent d'une façon continue une quantité prédéterminée de principe actif.When preparing a solid composition in the form of tablets, it is mixed the main active ingredient with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. We can coat the tablets with sucrose or other suitable materials or you can treat them so that they have prolonged or delayed activity and they release continuously a predetermined amount of active ingredient.

    On obtient une préparation en gélules en mélangeant l'ingrédient actif avec un diluant et en versant le mélange obtenu dans des gélules molles ou dures. A preparation in capsules is obtained by mixing the active ingredient with a diluting and pouring the mixture obtained into soft or hard capsules.

    Une préparation sous forme de sirop ou d'elixir peut contenir l'ingrédient actif conjointement avec un édulcorant, acalorique de préférence, du méthylparaben et du propylparaben comme antiseptiques, ainsi qu'un agent donnant du goût et un colorant approprié.A preparation in the form of syrup or elixir may contain the active ingredient together with a sweetener, preferably calorie-free, methylparaben and propylparaben as antiseptics, as well as a flavoring agent and a color appropriate.

    Les poudres ou les granulés dispersibles dans l'eau peuvent contenir l'ingrédient actif en mélange avec des agents de dispersion ou des agents mouillants, ou des agents de mise en suspension, comme la polyvinylpyrrolidone, de même qu'avec des édulcorants ou des correcteurs du goût.Water dispersible powders or granules may contain the ingredient active in admixture with dispersing agents or wetting agents, or agents suspension, such as polyvinylpyrrolidone, as well as with sweeteners or flavor correctors.

    Pour une administration locale, on mélange le principe actif dans un excipient pour la préparation de crèmes ou onguents ou on le dissout dans un véhicule pour l'administration intraoculaire, par exemple sous forme de collyre.For local administration, the active ingredient is mixed in an excipient for the preparation of creams or ointments or it is dissolved in a vehicle for intraocular administration, for example in the form of eye drops.

    Pour une administration rectale, on recourt à des suppositoires qui sont préparés avec des liants fondant à la température rectale, par exemple du beurre de cacao ou des polyéthylèneglycols.Suppositories are used for rectal administration. with binders that melt at the rectal temperature, for example cocoa butter or polyethylene glycols.

    Pour une administration parentérale, on utilise des suspensions aqueuses, des solutions salines ou des solutions stériles et injectables qui contiennent des agents de dispersion et/ou des mouillants pharmacologiquement compatibles, par exemple le propylèneglycol ou le butylèneglycol.For parenteral administration, aqueous suspensions, saline or sterile and injectable solutions that contain dispersion and / or pharmacologically compatible wetting agents, for example propylene glycol or butylene glycol.

    Le principe actif peut être formulé également sous forme de microcapsules, éventuellement avec un ou plusieurs supports ou additifs.The active principle can also be formulated in the form of microcapsules, possibly with one or more supports or additives.

    Selon un autre de ses aspects, la présente invention concerne une méthode de traitement des pathologies qui sont améliorées par une action β3-agoniste, qui comprend administrer un composé de formule (I) ou (Ia) ou l'un de ses sels ou solvates pharmaceutiquement acceptables.According to another of its aspects, the present invention relates to a method of treatment of pathologies which are improved by a β 3 -agonist action, which comprises administering a compound of formula (I) or (Ia) or one of its salts or pharmaceutically acceptable solvates.

    Les composés de formule (I) et (Ia), notamment les composés (I) et (Ia) marquées par un isotope, peuvent aussi être utilisés comme outils de laboratoire dans des essais biochimiques.The compounds of formula (I) and (Ia), in particular the compounds (I) and (Ia) marked with an isotope, can also be used as laboratory tools in biochemical tests.

    Les composés de formule (I) et (Ia) se lient au récepteur β3-adrénergique. On βpeut donc utiliser ces composés dans un essai ordinaire de liaison ("binding"), dans lequel on emploie un tissu organique où ce récepteur est particulièrement abondant, et on mesure la quantité de composé (I) ou (Ia) déplacé par un composé test, pour évaluer l'affinité dudit composé vis-à-vis des sites de liaison de ce récepteur particulier.The compounds of formula (I) and (Ia) bind to the β 3 -adrenergic receptor. We can therefore use these compounds in an ordinary binding test, in which an organic tissue is used where this receptor is particularly abundant, and the quantity of compound (I) or (Ia) displaced by a compound is measured. test, to assess the affinity of said compound vis-à-vis the binding sites of this particular receptor.

    Un autre objet spécifique de la présente invention est donc un réactif utilisable dans les essais biochimiques, qui comprend au moins un composé de formule (I) ou (Ia) convenablement marqué.Another specific object of the present invention is therefore a reagent which can be used in biochemical tests, which comprises at least one compound of formula (I) or (Ia) suitably marked.

    Les exemples qui suivent illustrent mieux l'invention.The examples which follow illustrate the invention better.

    PREPARATION 1PREPARATION 1 4-tert-butoxycarbonylamino-pipéridine.4- tert -butoxycarbonylamino-piperidine.

    On mélange à la température ambiante pendant 2 heures 25 g (0,13 mole) de 4-amino-1-benzylpipéridine, 36,2 ml (0,26 mole) de triéthylamine et 31,2 g (0,143 mole) de di-tert-butyl-dicarbonate dans 200 ml de diméthylformamide. On verse le mélange dans de l'eau, on extrait à l'acétate d'éthyle, on lave à l'eau et on cristallise le produit ainsi obtenu dans 200 ml d'éther isopropylique. On obtient 33 g de 1-benzyl-4-tert-butoxycarbonylamino-pipéridine qu'on hydrogène dans un mélange de 200 ml d'éthanol et 100 ml de tétrahydrofurane en présence de 3 g de Pd/C à 10%. Après filtration du catalyseur, on isole le composé du titre. P.f. 157-160°C.25 g (0.13 mole) of 4-amino-1-benzylpiperidine, 36.2 ml (0.26 mole) of triethylamine and 31.2 g (0.143 mole) of di- are mixed at room temperature for 2 hours. tert -butyl-dicarbonate in 200 ml of dimethylformamide. The mixture is poured into water, extracted with ethyl acetate, washed with water and the product thus obtained is crystallized from 200 ml of isopropyl ether. 33 g of 1-benzyl-4- tert -butoxycarbonylamino-piperidine are obtained, which is hydrogenated in a mixture of 200 ml of ethanol and 100 ml of tetrahydrofuran in the presence of 3 g of 10% Pd / C. After filtration of the catalyst, the title compound is isolated. Mp 157-160 ° C.

    PREPARATION 2PREPARATION 2 4-tert-butoxycarbonylaminométhyl-pipéridine.4- tert -butoxycarbonylaminomethyl-piperidine.

    En opérant comme décrit dans la préparation 1, mais en utilisant la 4-aminométhyl-1-benzylamine au lieu de la 4-amino-1-benzylamine, on obtient le composé du titre. P.f. 105-107°C.By operating as described in preparation 1, but using 4-aminomethyl-1-benzylamine instead of 4-amino-1-benzylamine, we get the composed of the title. Mp 105-107 ° C.

    EXEMPLE 1EXAMPLE 1 4-tert-butoxycarbonylamino-1-(5-aminocarbonylpyridi-2-yl)-pipéridine.4- tert -butoxycarbonylamino-1- (5-aminocarbonylpyridi-2-yl) -piperidine.

    On chauffe à 80°C pendant 18 heures un mélange de 3 g (0,015mole) du produit de la préparation 1, 1,5 g (0,015 mole) de triéthylamine et 2,34 g (0,015 mole) de 6-chloronicotinamide dans 60 ml de diméthylformamide. Après refroidissement on ajoute de l'eau et on filtre le produit. On obtient ainsi 2,8 g du composé du titre. P.f. 255°C déc.A mixture of 3 g (0.015 mol) of the product is heated at 80 ° C. for 18 hours. of preparation 1, 1.5 g (0.015 mole) of triethylamine and 2.34 g (0.015 mole) of 6-chloronicotinamide in 60 ml of dimethylformamide. After cooling, add water and the product is filtered. 2.8 g of the title compound are thus obtained. Mp 255 ° C dec.

    EXEMPLE 2EXAMPLE 2 4-amino-1-(5-aminocarbonylpyrid-2-yl)-pipéridine et son dichlorhydrate hémihydraté.4-amino-1- (5-aminocarbonylpyrid-2-yl) -piperidine and its dihydrochloride hemihydrate.

    On mélange 1,84 g (0,0057 mole) du produit de l'exemple 1 et 50 ml d'acétate d'éthyle.1.84 g (0.0057 mole) of the product of Example 1 and 50 ml of acetate are mixed ethyl.

    On y ajoute 50 ml d'une solution 3N d'acide chlorhydrique dans de l'acétate d'éthyle sous agitation et on laisse agiter à la température ambiante pendant 10 heures. On filtre et on lave à l'acétone. On obtient ainsi 1,67 g du composé du titre. P.f. 290°C déc.50 ml of a 3N solution of hydrochloric acid in acetate are added thereto. ethyl with stirring and allowed to stir at room temperature for 10 hours. It is filtered and washed with acetone. 1.67 g of the title compound are thus obtained. Mp 290 ° C. Dec.

    EXEMPLE 3EXAMPLE 3 4-tert-butoxycarbonylamino-1-(5-éthoxycarbonylpyrid-2-yl)-pipéridine.4- tert -butoxycarbonylamino-1- (5-ethoxycarbonylpyrid-2-yl) -piperidine.

    On fait réagir un mélange comme décrit dans l'exemple 1 mais en utilisant l'ester éthylique de l'acide 6-chloronicotinique au lieu du 6-chloronicotinamide. Après refroidissement, on y ajoute de l'eau, on extrait l'acétate d'éthyle, on sèche la phase organique sur du sulfate de sodium et on évapore le solvant sous pression réduite. On obtient le composé du titre. P.f. 140-142°C.A mixture is reacted as described in Example 1 but using the ester 6-chloronicotinic acid ethyl instead of 6-chloronicotinamide. After cooling, water is added thereto, the ethyl acetate is extracted, the phase is dried organic over sodium sulfate and the solvent is evaporated off under reduced pressure. We obtains the title compound. Mp 140-142 ° C.

    EXEMPLE 4EXAMPLE 4 4-amino-1-(5-éthoxycarbonylpyrid-2-yl)-pipéridine et son dichlorhydrate hydraté.4-amino-1- (5-ethoxycarbonylpyrid-2-yl) -piperidine and its hydrated dihydrochloride.

    En opérant comme décrit dans l'exemple 2 mais en utilisant le produit de l'exemple 3 au lieu du produit de l'exemple 1, on obtient le composé du titre. P.f. 148-150°C.By operating as described in Example 2 but using the product of Example 3 instead of the product of Example 1, the title compound is obtained. Mp 148-150 ° C.

    EXEMPLE 5EXAMPLE 5 4-tert-butoxycarbonylamino-1-(5-nitropyrid-2-yl)-pipéridine.4- tert -butoxycarbonylamino-1- (5-nitropyrid-2-yl) -piperidine.

    En opérant comme décrit dans l'exemple 1 mais en utilisant la 2-chloro-5-nitropyridine au lieu du 6-chloronicotinamide, on obtient le composé du titre. P.f. 220°C.By operating as described in Example 1 but using 2-chloro-5-nitropyridine instead of 6-chloronicotinamide, the title compound is obtained. Mp 220 ° C.

    EXEMPLE 6EXAMPLE 6 4-amino-1-(5-nitropyrid-2-yl)-pipéridine.4-amino-1- (5-nitropyrid-2-yl) -piperidine.

    En opérant comme décrit dans l'exemple 2 mais en utilisant le produit de l'exemple 5 au lieu du produit de l'exemple 1, on obtient le chlorhydrate composé du titre. P.f. 266-270°C.By operating as described in Example 2 but using the product of example 5 instead of the product of example 1, the hydrochloride compound of title. Mp 266-270 ° C.

    On libère la base à l'aide d'une solution de H2O/NH4OH et extraction à l'acétate d'éthyle. On obtient le composé du titre. P.f. 115-117°C.The base is released using an H 2 O / NH 4 OH solution and extraction with ethyl acetate. The title compound is obtained. Mp 115-117 ° C.

    EXEMPLE 7EXAMPLE 7 4-tert-butoxycarbonylamino-1-(5-cyanopyrid-2-yl)-pipéridine.4- tert -butoxycarbonylamino-1- (5-cyanopyrid-2-yl) -piperidine.

    En opérant comme décrit dans l'exemple 1 mais en utilisant la 2-chloro-5-cyanopyridine au lieu du 6-chloronicotinamide, on obtient le composé du titre. P.f. 192-194°C.By operating as described in Example 1 but using 2-chloro-5-cyanopyridine instead of 6-chloronicotinamide, the title compound is obtained. Mp 192-194 ° C.

    EXEMPLE 8EXAMPLE 8 4-amino-1-(5-cyanopyrid-2-yl)-pipéridine.4-amino-1- (5-cyanopyrid-2-yl) -piperidine.

    En opérant comme décrit dans l'exemple 2 mais en utilisant le produit de l'exemple 7 au lieu du produit de l'exemple 1, et en traitant le sel chlorhydrate ainsi obtenu avec une solution aqueuse de NH4OH, on obtient le composé du titre. P.f. 68-72°C.By operating as described in Example 2 but using the product of Example 7 instead of the product of Example 1, and treating the hydrochloride salt thus obtained with an aqueous solution of NH 4 OH, the compound is obtained of the title. Mp 68-72 ° C.

    EXEMPLE 9EXAMPLE 9 9a/ 3-[1-(5-aminocarbonylpyrid-2-yl)-4-pipéridinylamino]-1-(4-benzyloxyphénoxy)-2-propanol.9a / 3- [1- (5-aminocarbonylpyrid-2-yl) -4-piperidinylamino] -1- (4-benzyloxyphenoxy) -2-propanol.

    On mélange 1,2 g (0,0054 mole) du produit de l'exemple 2 (base), 1,4 g (0,0054 mole) de 4-benzyloxy-1-(2,3-époxypropoxy)benzène dans 50 ml de diméthylsulfoxyde et on chauffe à 70°C pendant 18 heures. On verse dans de l'eau, on extrait à l'acétate d'éthyle, on sèche, on filtre et on évapore le solvant sous pression réduite. On obtient le composé du titre. P.f. 160-162°C.1.2 g (0.0054 mole) of the product of Example 2 (base) are mixed, 1.4 g (0.0054 mole) of 4-benzyloxy-1- (2,3-epoxypropoxy) benzene in 50 ml of dimethyl sulfoxide and heated at 70 ° C for 18 hours. Pour into water, extract with acetate ethyl, dried, filtered and the solvent is evaporated off under reduced pressure. We get the composed of the title. Mp 160-162 ° C.

    9b/ 3-[1-(5-aminocarbonylpyrid-2-yl)-4-pipéridinylamino]-1-(4-hydroxy phénoxy)-2-propanol.9b / 3- [1- (5-aminocarbonylpyrid-2-yl) -4-piperidinylamino] -1- (4-hydroxy phenoxy) -2-propanol.

    On hydrogène 0,77 g du composé de l'étape précédente à 40 °C à la pression ambiante dans 30 ml de THF et 30 ml d'éthanol en présence de 0,1 g de Pd/C à 10% pendant 6 heures environ. On filtre le catalyseur et on évapore sous pression réduite. On purifie le brut de réaction par flash-chromatographie en éluant par un mélange chlorure de méthylène/méthanol = 8/2. On obtient le composé du titre. P.f. 192-194°C0.77 g of the compound from the previous step is hydrogenated at 40 ° C at pressure ambient in 30 ml of THF and 30 ml of ethanol in the presence of 0.1 g of Pd / C at 10% for about 6 hours. The catalyst is filtered and evaporated under reduced pressure. We purifies the reaction crude by flash chromatography, eluting with a chloride mixture methylene / methanol = 8/2. The title compound is obtained. Mp 192-194 ° C

    EXEMPLE 10EXAMPLE 10 3-[1-(5-éthoxycarbonylpyrid-2-yl)-4-pipéridinylamino]-1-(4-hydroxyphénoxy)-2-propanol.3- [1- (5-éthoxycarbonylpyrid-2-yl) -4-piperidinylamino] -1- (4-hydroxyphenoxy) -2-propanol.

    En opérant comme décrit dans l'exemple 9 mais en utilisant le produit de l'exemple 4 au lieu du produit de l'exemple 2, on obtient le composé du titre. P.f. 157-159°CBy operating as described in Example 9 but using the product of Example 4 instead of the product of Example 2, the title compound is obtained. Mp 157-159 ° C

    EXEMPLE 11EXAMPLE 11 3-[1-(5-cyanopyrid-2-yl)-4-pipéridinylamino]-1-(4-hydroxyphénoxy)-2-propanol.3- [1- (5-cyanopyrid-2-yl) -4-piperidinylamino] -1- (4-hydroxyphenoxy) -2-propanol.

    En opérant comme décrit dans l'exemple 9 mais en utilisant le produit de l'exemple 8 au lieu du produit de l'exemple 2, on obtient le composé du titre. P.f. 160-162°C.By operating as described in Example 9 but using the product of Example 8 instead of the product of Example 2, the title compound is obtained. Mp 160-162 ° C.

    EXEMPLE 12EXAMPLE 12 3-[1-(5-nitropyrid-2-yl)-4-pipéridinylamino)-1-(4-hydroxyphénoxy)-2-propanol.3- [1- (5-nitropyrid-2-yl) -4-piperidinylamino) -1- (4-hydroxyphenoxy) -2-propanol. 12a/ 3-[1-(5-nitropyrid-2-yl)-4-pipéridinylamino]-1-4-méthoxy-éthoxy-méthoxy phénoxy)-2-propanol.12a / 3- [1- (5-nitropyrid-2-yl) -4-piperidinylamino] -1-4-methoxy-ethoxy-methoxy phenoxy) -2-propanol.

    On chauffe au reflux pendent 17 heures un mélange de 1,06 g (0,0048 mole) du produit de l'exemple 6 et de 1,21 g (0,0048 mole) de 4-(méthoxy-éthoxy-méthoxy)-1-(2,3-époxypropoxy)-benzène dans 40 ml d'éthanol. On filtre et on cristallise le produit dans 25 ml d'éthanol absolu. On obtient ainsi le composé du titre. P.f. 122-124°C.The mixture is refluxed for 17 hours for a mixture of 1.06 g (0.0048 mole) of product of Example 6 and 1.21 g (0.0048 mole) of 4- (methoxy-ethoxy-methoxy) -1- (2,3-epoxypropoxy) -benzene in 40 ml of ethanol. Filter and crystallize the product in 25 ml of absolute ethanol. The title compound is thus obtained. Mp 122-124 ° C.

    12b/ 3-[1-(5-nitropyrid-2-yl)-4-pipéridinylamino]-1-(4-hydroxyphénoxy)-2-propanol.12b / 3- [1- (5-nitropyrid-2-yl) -4-piperidinylamino] -1- (4-hydroxyphenoxy) -2-propanol.

    A une solution de 1,2 g (0,0025 mole) du produit de l'étape précédente dans 10 ml de chlorure de méthylène, on ajoute 2 ml de CF3COOH dans 5 ml de chlorure de méthylène. On agite à la température ambiante pendant 48 heures. On verse le mélange dans de l'eau, on y ajoute une solution de H2O/NH4OH jusqu'à un pH basique, on extrait à l'acétate d'éthyle et on évapore le solvant sous pression réduite. On purifie par flash-chromatographie (éluant: chlorure de méthylène/méthanol = 9/1. On obtient le composé du titre. P.f. 195-197°C.To a solution of 1.2 g (0.0025 mole) of the product of the previous step in 10 ml of methylene chloride, 2 ml of CF 3 COOH in 5 ml of methylene chloride are added. Stir at room temperature for 48 hours. The mixture is poured into water, an H 2 O / NH 4 OH solution is added thereto to a basic pH, the mixture is extracted with ethyl acetate and the solvent is evaporated off under reduced pressure. Purification is carried out by flash chromatography (eluent: methylene chloride / methanol = 9/1. The title compound is obtained. Mp 195-197 ° C.

    EXEMPLE 13EXAMPLE 13 4-tert-butoxycarbonylamino-1-(4-éthoxycarbonylpyrid-2-yl)-pipéridine.4- tert -butoxycarbonylamino-1- (4-ethoxycarbonylpyrid-2-yl) -piperidine.

    En opérant comme décrit dans l'exemple 3 mais en utilisant l'ester éthylique de l'acide 2-chloro-4-pyridincarboxylique au lieu de l'ester éthylique de l'acide 6-chloronicotinique, on obtient le composé du titre. P.f. 105-107°C. By operating as described in Example 3 but using the ethyl ester of 2-chloro-4-pyridincarboxylic acid instead of the ethyl ester of 6-chloronicotinic acid, the title compound is obtained. Mp 105-107 ° C.

    EXEMPLE 14EXAMPLE 14 4-amino-1-(4-éthoxycarbonylpyrid-2-yl)-pipéridine et son dichlorhydrate hydraté.4-amino-1- (4-ethoxycarbonylpyrid-2-yl) -piperidine and its hydrated dihydrochloride.

    En opérant comme décrit dans l'exemple 2 mais en utilisant le produit de l'exemple 13 au lieu du produit de l'exemple 1, on obtient le composé du titre. P.f. 222-224°C déc.By operating as described in Example 2 but using the product of Example 13 instead of the product of Example 1, the title compound is obtained. Mp 222-224 ° C Dec.

    EXEMPLE 15EXAMPLE 15 3-[1-(4-éthoxycarbonylpyrid-2-yl)-4-pipéridinylamino]-1-(4-hydroxyphénoxy)-2-propanol.3- [1- (4-éthoxycarbonylpyrid-2-yl) -4-piperidinylamino] -1- (4-hydroxyphenoxy) -2-propanol.

    En opérant comme décrit dans l'exemple 9 mais en utilisant le produit de l'exemple 14 (base), au lieu du produit de l'exemple 2, on obtient le composé du titre. P.f. 115-117 °C.By operating as described in Example 9 but using the product of Example 14 (base), instead of the product of Example 2, the title compound is obtained. Mp 115-117 ° C.

    EXEMPLE 16EXAMPLE 16 4-tert-butoxycarbonylamino-1-(pyrid-2-ylméthyl)-pipéridine.4- tert -butoxycarbonylamino-1- (pyrid-2-ylmethyl) -piperidine.

    En opérant comme décrit dans l'exemple 3 mais en utilisant la 2-chlorométhylpyridine au lieu de l'ester éthylique de l'acide 6-chloronicotinique, on obtient le composé du titre. P.f. 98-100°C.By operating as described in Example 3 but using 2-chloromethylpyridine instead of the ethyl ester of 6-chloronicotinic acid, we obtains the title compound. Mp 98-100 ° C.

    EXEMPLE 17EXAMPLE 17 4-amino-1-(pyrid-2-yl-méthyl)-pipéridine et son chlorhydrate dihydraté.4-amino-1- (pyrid-2-yl-methyl) -piperidine and its hydrochloride dihydrate.

    En opérant comme décrit dans l'exemple 2 mais en utilisant le produit de l'exemple 16 au lieu du produit de l'exemple 1, on obtient le composé du titre. P.f. 270-273°C.By operating as described in Example 2 but using the product of Example 16 instead of the product of Example 1, the title compound is obtained. Mp 270-273 ° C.

    EXEMPLE 18EXAMPLE 18 3-[1-(pyrid-2-yl-méthyl)-4-pipéridinylamino]-1-(4-hydroxy-phénoxy)-2-propanol.3- [1- (pyrid-2-yl-methyl) -4-piperidinylamino] -1- (4-hydroxy-phenoxy) -2-propanol.

    En opérant comme décrit dans l'exemple 9 mais en utilisant le produit de l'exemple 17 base au lieu du produit de l'exemple 2, on obtient le composé du titre. P.f. :190-192°C.By operating as described in Example 9 but using the product of Example 17 base instead of the product of Example 2, the title compound is obtained. Mp : 190-192 ° C.

    EXEMPLE 19EXAMPLE 19 4-tert-butoxycarbonylaminométhyl-1-(5-éthoxycarbonylpyrid-2-yl)-pipéridine.4- tert -butoxycarbonylaminomethyl-1- (5-ethoxycarbonylpyrid-2-yl) -piperidine.

    En opérant comme décrit dans l'exemple 3 mais en utilisant le produit de la préparation 2 au lieu du produit de la préparation 1, on obtient le composé du titre. P.f. 118-120°C.By operating as described in Example 3 but using the product of the preparation 2 instead of the product of preparation 1, the title compound is obtained. Mp 118-120 ° C.

    EXEMPLE 20EXAMPLE 20 4-aminométhyl-1-(5-éthoxycarbonylpyrid-2-yl)-pipéridine et son dichlorhydrate.4-aminomethyl-1- (5-ethoxycarbonylpyrid-2-yl) -piperidine and its dihydrochloride.

    En opérant comme décrit dans l'exemple 2 mais en utilisant mais en utilisant le produit de l'exemple 19 au lieu du produit de l'exemple 1, on obtient le composé du titre. P.f. 230-232°C. By operating as described in Example 2 but using but using the product of Example 19 instead of the product of Example 1, the compound of title. Mp 230-232 ° C.

    EXEMPLE 21EXAMPLE 21 3-{[1-(5-éthoxycarbonylpyrid-2-yl)-4-pipéridinylméthyl]amino}-1-(4-hydroxyphénoxy)-2-propanol (chlorhydrate).3 - {[1- (5-éthoxycarbonylpyrid-2-yl) -4-piperidinylmethyl] amino} -1- (4-hydroxyphenoxy) -2-propanol (Hydrochloride).

    En opérant comme décrit dans l'exemple 9 mais en utilisant le produit de l'exemple 20 (base) au lieu du produit de l'exemple 2, on obtient le composé du titre base. On prépare le chlohydrate à l'aide d'une solution d'acide chlorhydrique en isopropanol. On obtient le composé du titre. P.f. 195°C déc.By operating as described in Example 9 but using the product of Example 20 (base) instead of the product of Example 2, the title compound is obtained based. The hydrochloride is prepared using a hydrochloric acid solution in isopropanol. The title compound is obtained. Mp 195 ° C Dec.

    EXEMPLE 22EXAMPLE 22 4-tert-butoxycarbonylamino-1-(pyrid-2-yl)-piperidine.4- tert -butoxycarbonylamino-1- (pyrid-2-yl) -piperidine.

    En opérant comme décrit dans l'exemple 3 mais en utilisant la 2-bromo-pyridine au lieu de l'ester éthylique de l'acide 6-chloronicotinique on obtient le composé du titre. P.f. : 118-120°C.By operating as described in Example 3 but using 2-bromo-pyridine instead of the ethyl ester of 6-chloronicotinic acid, the title compound is obtained. Mp : 118-120 ° C.

    EXEMPLE 23EXAMPLE 23 4-amino-1-(pyrid-2-yl)-pipéridine et son chlorohydrate.4-amino-1- (pyrid-2-yl) -piperidine and its hydrochloride.

    En opérant comme décrit dans l'exemple 2 mais en utilisant le produit issu de l'exemple 22 on obtient le composé du titre. P.f. : 227-230°C.By operating as described in Example 2 but using the product from Example 22 gives the title compound. Mp : 227-230 ° C.

    EXEMPLE 24EXAMPLE 24 3-[1-(pyrid-2-yl)-4-pipéridinylamino]-1-(4-hydroxy-phénoxy)-2-propanol et son dichlorhydrate hydraté.3- [1- (pyrid-2-yl) -4-piperidinylamino] -1- (4-hydroxy-phenoxy) -2-propanol and its hydrated dihydrochloride.

    En opérant comme décrit dans l'exemple 9 mais en utilisant le produit de l'exemple 23 base au lieu du produit de l'exemple 2 et de l'éthanol absolu au lieu du diméthylsulfoxide on obtient le composé du titre base. On prépare le chlorydrate à l'aide d'une solution d'acide chlorhydrique en isopropanol. On obtient le composé du titre. P.f.: 137-139.By operating as described in Example 9 but using the product of Example 23 bases instead of the product of Example 2 and absolute ethanol instead of dimethylsulfoxide, the base title compound is obtained. We prepare the hydrochloride using of a hydrochloric acid solution in isopropanol. The title compound is obtained. P.f .: 137-139.

    EXEMPLE 25EXAMPLE 25 (2S)-3-[1-(5-éthoxycarbonylpyrid-2-yl)-4-pipéridinylamino]-1-(4-hydroxyphénoxy)-2-propanol.(2S) -3- [1- (5-éthoxycarbonylpyrid-2-yl) -4-piperidinylamino] -1- (4-hydroxyphenoxy) -2-propanol. 25a) (2S)-3-[1-(5-éthoxycarbonylpirid-2-yl)-4-pipéridinylamino]-1-(4-benzyloxy phénoxy)-2-propanol. 25a) (2S) -3- [1- (5-ethoxycarbonylpirid-2-yl) -4-piperidinylamino] -1- (4-benzyloxy phenoxy) -2-propanol.

    On mélange 0,81g (0,0033 mole) du produit de l'exemple 4 avec 0,83g (0,0033 mole) de (2S)-4-benzyloxy-1-(2,3-époxypropoxy)benzène dans 90 ml de éthanol et on chauffe au reflux pendant 20 heures. On évapore le solvant et on ajoute de l'éther éthylique. On filtre et on purifie le brut de réaction par chromatographie en éluant par un mélange chlorure de méthylène/méthanol = 95/5.0.81 g (0.0033 mole) of the product of Example 4 is mixed with 0.83 g (0.0033 mole) of (2S) -4-benzyloxy-1- (2,3-epoxypropoxy) benzene in 90 ml of ethanol and heats at reflux for 20 hours. The solvent is evaporated off and ether is added ethyl. The reaction crude is filtered and purified by chromatography, eluting with a methylene chloride / methanol mixture = 95/5.

    On obtient le composé du titre. P.f. : 105-107°C; [αD] = -5,12° (C = 1% en CHCl3).The title compound is obtained. Mp: 105-107 ° C; [α D ] = -5.12 ° (C = 1% CHCl 3 ).

    25b) (2S)-3-[1-(5-éthoxycarbonylpyrid-2-yl)-4-pipéridinylamino]-1-(4-hydroxyphénoxy)-2-propanol.25b) (2S) -3- [1- (5-ethoxycarbonylpyrid-2-yl) -4-piperidinylamino] -1- (4-hydroxyphenoxy) -2-propanol.

    Le produit issu de l'étape précédente est soumis à une hydrogénation selon la procédure décrite dans l'exemple 9b. Le brut de réaction est purifié par flash-chromatographie en éluant par un mélange chlorure de méthylène/méthanol = 95:5. On obtient le composé du titre. P.f.. 135-137 °C, [αD] = 5,64 (C=1% en CH3OH).The product from the previous step is subjected to hydrogenation according to the procedure described in Example 9b. The crude reaction product is purified by flash chromatography, eluting with a methylene chloride / methanol mixture = 95: 5. The title compound is obtained. Mp 135-137 ° C, [α D ] = 5.64 (C = 1% CH 3 OH).

    EXEMPLE 26EXAMPLE 26 26a) 3-[1-(5-éthoxycarbonylpyrid-2-yl)-4-pipéridinylamino]-1-[(4-benzyloxy-3-méthylsulfinyl)-phénoxy]-2-propanol. 26a) 3- [1- (5-ethoxycarbonylpyrid-2-yl) -4-piperidinylamino] -1 - [(4-benzyloxy-3-methylsulfinyl) -phenoxy] -2-propanol.

    On mélange 0,75 g (0,0024 mole) de 4-benzyloxy-3-méthylsulfinyl-1-(2,3 époxypropoxy)benzène (préparé selon le procédé décrit dans US 4,396,629) avec 0,646 g (0,0026 mole) du produit de l'exemple 4 base dans éthanol absolu. On chauffe au reflux pendant 4 heures, on sèche et on purifie le brut de réaction par chromatographie en éluant avec des mélanges de CH2Cl2, CH3OH, NH4OHconc en proportion variables entre 95 :5 :0,2 et 90 :10 :1. On obtient le produit de réaction. P.f. : 113-130 °C.0.75 g (0.0024 mole) of 4-benzyloxy-3-methylsulfinyl-1- (2,3 epoxypropoxy) benzene (prepared according to the method described in US 4,396,629) is mixed with 0.646 g (0.0026 mole) of the product of Example 4 base in absolute ethanol. The mixture is heated at reflux for 4 hours, dried and the reaction crude is purified by chromatography, eluting with mixtures of CH 2 Cl 2 , CH 3 OH, NH 4 OH, in variable proportions between 95: 5: 0.2 and 90 : 10: 1. The reaction product is obtained. Mp: 113-130 ° C.

    26b) 3-[1-(5-éthoxycarbonylpyrid-2-yl)-4-pipéridinylamino]-1-[(4-hydroxy-3-méthylsulfinyl)-phenoxy]-2-propanol et son dichlorohydrate dihydraté 26b) 3- [1- (5-ethoxycarbonylpyrid-2-yl) -4-piperidinylamino] -1 - [(4-hydroxy-3-methylsulfinyl) -phenoxy] -2-propanol and its dihydrochloride dihydrate

    On chauffe le produit de l'étape précédente pendant 7 heures à 55°C dans 20 ml de CF3COOH. On évapore partiellement le solvant, on ajoute de l'acétate d'éthyle et du toluène et on évapore encore le solvant. On ajoute de l'eau sature en Na2CO3 et on extrait à l'acétate d'éthyle. Le brut de réaction est séché et purifié par flash-chromatographie en éluant par un mélange de CH2Cl2, CH3OH, NH4OHconc en proportions variables entre 92 :8 :0,8 et 90:10 :1. On obtient le composé du titre comme base libre (P.f. : 95-100°C). On dissout le produit dans l'acétone et on ajoute une solution de HCl en isopropanol, on filtre et on lave à l'acétone. On obtient le produit du titre. P.f. :173-175°C.The product from the previous step is heated for 7 hours at 55 ° C in 20 ml of CF 3 COOH. The solvent is partially evaporated, ethyl acetate and toluene are added and the solvent is further evaporated. Water saturated with Na 2 CO 3 is added and the mixture is extracted with ethyl acetate. The crude reaction product is dried and purified by flash chromatography, eluting with a mixture of CH 2 Cl 2 , CH 3 OH, NH 4 OH, in variable proportions between 92: 8: 0.8 and 90:10: 1. The title compound is obtained as a free base (mp: 95-100 ° C). The product is dissolved in acetone and an HCl solution isopropanol is added, filtered and washed with acetone. The title product is obtained. Mp: 173-175 ° C.

    EXEMPLE 27EXAMPLE 27 4-tert butoxycarbonylamino-1-(5-méthylpyrid-2-yl)pipéridine.4- tert- butoxycarbonylamino-1- (5-methylpyrid-2-yl) piperidine.

    On chauffe à 130°C pendant une nuit 2,03g (0,0101 mole) du produit de la préparation 1 avec 3,5 g (0,0203 mole) de 2-bromo-5-méthylpyridine et 1,5 ml de triéthylamine dans 50 ml de diméthylsulfoxide. On verse dans l'eau, on extrait le brut de réaction qui est purifié par flash-chromatographie (cyclohéxane/éthyleacétate = 1/3). P.f. : 121-123°C.Heated to 130 ° C overnight 2.03g (0.0101 mole) of the product preparation 1 with 3.5 g (0.0203 mole) of 2-bromo-5-methylpyridine and 1.5 ml of triethylamine in 50 ml of dimethylsulfoxide. We pour in water, extract the crude reaction which is purified by flash chromatography (cyclohexane / ethyl acetate = 1/3). Mp : 121-123 ° C.

    EXEMPLE 28EXAMPLE 28 4-amino-1-(5-méthylpyrid-2-yl)-pipéridine et son dichlorhydrate hydraté.4-amino-1- (5-methylpyrid-2-yl) -piperidine and its hydrated dihydrochloride.

    On chauffe au reflux pendant 4 heures une solution contenant le produit de l'exemple 27 dans 18 ml de éthyle acétate et 18 ml de HCl en éthyle acétate (environ 3N). On filtre et on lave à l'acétone. On cristallise en isopropanol et on obtient le composé du titre. P.f.: 281-283 °C. A solution containing the product is heated at reflux for 4 hours. Example 27 in 18 ml of ethyl acetate and 18 ml of HCl in ethyl acetate (approximately 3N). It is filtered and washed with acetone. It is crystallized from isopropanol and the composed of the title. M.p .: 281-283 ° C.

    EXEMPLE 29EXAMPLE 29 29a) 3-[1-(5-méthylpyrid-2-yl)-4-pipéridinylamino)-1-(4-benzyloxyphénoxy)-2-propanol. 29a) 3- [1- (5-methylpyrid-2-yl) -4-piperidinylamino) -1- (4-benzyloxyphenoxy) -2-propanol.

    On chauffe au reflux pendant une nuit 1,81 g (0,00956 mole) du produit de l'exemple 28 et 2,2 g (0,00860 mole)de 4-benzyloxy-1-(2,3-époxyproxy)-benzène dans 100 ml d'éthanol absolu. On évapore le solvant et on purifie le brut de réaction par flash-chromatographie en éluant par un mélange cyclohéxane/éthyle acétate = 6/4 et par le suite métahnol/ammoniac = 100/1. On obtient le produit du titre. P.f. 123-125°C.1.81 g (0.00956 mole) of the product is heated at reflux overnight. Example 28 and 2.2 g (0.00860 mole) of 4-benzyloxy-1- (2,3-epoxyproxy) -benzene in 100 ml of absolute ethanol. The solvent is evaporated and the reaction crude is purified by flash chromatography eluting with a cyclohexane / ethyl acetate mixture = 6/4 and with metahnol / ammonia sequence = 100/1. The title product is obtained. Mp 123-125 ° C.

    29b) 3-[1-(5-méthylpyrid-2-yl)-4-pipéridinylamino]-1-(4-hydroxyphénoxy)-2-propanol et son dichlorydrate. 29b) 3- [1- (5-methylpyrid-2-yl) -4-piperidinylamino] -1- (4-hydroxyphenoxy) -2-propanol and its dichlorydrate.

    On opère comme décrit en 29b mais on utilise le produit de l'exemple 29a. Le brut de réaction est purifié par flash-chromatographie en éluant par un mélange éthyl acétate/méthanol = 4.6. On obtient le composé du titre comme base. On prépare le chlorhydrate par addition de HCl en isopropanol. P.f. : 151-153 °C.The procedure is as described in 29b but the product of Example 29a is used. The crude reaction product is purified by flash chromatography, eluting with an ethyl mixture acetate / methanol = 4.6. The title compound is obtained as the base. We prepare the hydrochloride by addition of HCl to isopropanol. Mp : 151-153 ° C.

    EXEMPLE 30EXAMPLE 30 4-tert-butoxycarbonylamino-1-(5-méthoxycarbonyl-pyrid-2-ylméthyl)-piperidine4-tert-butoxycarbonylamino-1- (5-methoxycarbonyl-pyrid-2-ylmethyl) -piperidine

    On chauffe à 40 °C pendant 2 heures une solution contenant 0,7 g (0,0034 mole) du produit de la préparation 1, 0,53 g (0,0023 mole) de 2-bromométhyl-5-méthoxycarbonyl-pyridine (préparée selon la procédure décrite en J. Med. Chem., 1992, 3, 490-501), 0,26 ml (0,0025 mole) de triéthylamine dans 10 ml de diméthylformamide. On verse dans l'eau, on extrait à l'acétate d'éthyle et on purifie le brut de réaction par flash-chromatographie (éluant acétate d'éthyle). On obtient le composé du titre. P.f. : 110-112 °C.A solution containing 0.7 g (0.0034 mole) is heated at 40 ° C. for 2 hours. of the product of preparation 1, 0.53 g (0.0023 mol) of 2-bromomethyl-5-methoxycarbonyl-pyridine (prepared according to the procedure described in J. Med. Chem., 1992, 3, 490-501), 0.26 ml (0.0025 mole) of triethylamine in 10 ml of dimethylformamide. Pour into water, extract with ethyl acetate and purify the reaction crude by flash chromatography (eluent ethyl acetate). The title compound is obtained. Mp : 110-112 ° C.

    EXEMPLE 31EXAMPLE 31 4-amino-1-(5-méthoxycarbonyl-pyrid-2-ylméthyl)-pipéridine4-amino-1- (5-methoxycarbonyl-pyrid-2-ylmethyl) -piperidine

    Le produit de l'exemple 30 est chauffé pendant 3 heures à 40 °C dans une solution de CH2Cl2 contenant 11 ml de CF3 COOH. On évapore le solvant et on cristallise en acétone. On obtient le produit du titre. P.f.: 173°-175°C.The product of Example 30 is heated for 3 hours at 40 ° C in a CH 2 Cl 2 solution containing 11 ml of CF 3 COOH. The solvent is evaporated and crystallized from acetone. The title product is obtained. Mp: 173 ° -175 ° C.

    EXEMPLE 32EXAMPLE 32 3-[1-(5-méthoxycarbonyl-pyrid-2-ylméthyl)-4-pipéridinylamino]-1-(4-hydroxy phénoxy)-2-propanol3- [1- (5-methoxycarbonyl-pyrid-2-ylmethyl) -4-piperidinylamino] -1- (4-hydroxy phenoxy) -2-propanol

    On opérant comme décrit dans l'exemple 12 mais en utilisant le produit de l'exemple 31 au lieu du produit de l'exemple 6 on obtient le produit du titre. P.f. : 141-143 °C.The procedure is as described in Example 12 but using the product of Example 31 instead of the product of Example 6, the title product is obtained. Mp : 141-143 ° C.

    EXEMPLE 33EXAMPLE 33 4-tert-butoxycarbonylaminométhyl-1-(5-méthoxycarbonyl-pyrid-2-ylméthyl)-piperidine4-tert-butoxycarbonylaminomethyl-1- (5-methoxycarbonyl-pyrid-2-ylmethyl) -piperidine

    On chauffe pendant deux heures dans 25 ml de diméthylformammide 1.68 g (0,0078 mole) du produit de la préparation 2, 1 ml (0,0068 mole) de triéthylamine et 1,5 g (0,0065 mole) de 2-bromométhyl-5-méthoxycarbonyl-pyridine. On verse dans l'eau, on extrait à l'acétate d'éthyle, on lave à l'eau et on sèche le produit. On cristallise en éther isoprophylique. P.f. : 103-105°C.It is heated for two hours in 25 ml of dimethylformammide 1.68 g (0.0078 mole) of the product of preparation 2, 1 ml (0.0068 mole) of triethylamine and 1.5 g (0.0065 mole) of 2-bromomethyl-5-methoxycarbonyl-pyridine. We pour into the water, extracted with ethyl acetate, washed with water and dried the product. We crystallize in isoprophylic ether. Mp : 103-105 ° C.

    EXEMPLE 34EXAMPLE 34 4-aminométhyl-1-(5-méthoxycarbonyl-pyrid-2-ylméthyl)-pipéridine trifuorocétate4-aminomethyl-1- (5-methoxycarbonyl-pyrid-2-ylmethyl) -piperidine trifuorocetate

    On chauffe à 40 °C pendant 3 heures une solution contenant 1,7 g (0,0046 mole) du produit de l'exemple 33, 15 ml de CF3COOH et 15 ml de CH2Cl2. On évapore le solvant sous vide, on ajoute de l'ammoniac concentré et on extrait à l'éthyl acétate. On évapore le solvant et on obtient le produit du titre. P.f. : 193-195 °C.A solution containing 1.7 g (0.0046 mole) of the product of Example 33, 15 ml of CF 3 COOH and 15 ml of CH 2 Cl 2 is heated at 40 ° C. for 3 hours. The solvent is evaporated in vacuo, concentrated ammonia is added and extraction is carried out with ethyl acetate. The solvent is evaporated off and the title product is obtained. Mp: 193-195 ° C.

    EXEMPLE 35EXAMPLE 35 3-[1-(5-méthoxycarbonyl-pyrid-2-ylméthyl)-4-pipéridinylaminométhyl]-1-(4-hydroxyphénoxy)-2-propanol3- [1- (5-methoxycarbonyl-pyrid-2-ylmethyl) -4-pipéridinylaminométhyl] -1- (4-hydroxyphenoxy) -2-propanol

    En opérant comme décrit dans l'exemple 9 mais en utilisant le produit de l'exemple 34 au lieu du produit de l'exemple 2 on obtient le composé du titre.By operating as described in Example 9 but using the product of Example 34 instead of the product of Example 2, the title compound is obtained.

    EXEMPLE 36EXAMPLE 36 (2R)-3-[5-éthoxycarbonylpyrid-2-yl)-4-pipéridinylamino]-1-(4-hydroxy-phénoxy)-2-propanol.(2R) -3- [5-éthoxycarbonylpyrid-2-yl) -4-piperidinylamino] -1- (4-hydroxy-phenoxy) -2-propanol.

    En opérant comme décrit dans l'exemple 25 mais en utilisant la (2R)-4-benzyloxy-1-(2,3-époxypropoxy)benzène au lieu de la (2S)-4-benzyloxy-1-(2,3-époxypropoxy)benzène on obtient le composé du titre. P.f. : 134°-135°C. [α]D= +4,2° (C= 1% en CH3OH)By operating as described in Example 25 but using (2R) -4-benzyloxy-1- (2,3-epoxypropoxy) benzene instead of (2S) -4-benzyloxy-1- (2,3- epoxypropoxy) benzene the title compound is obtained. Mp: 134 ° -135 ° C. [α] D = + 4.2 ° (C = 1% CH 3 OH)

    EXEMPLE 37EXAMPLE 37 (2S)-4-benzyloxy-3-méthylsulfinyl-1-(2,3-époxypropropoxy)benzène.(2S) -4-benzyloxy-3-methylsulfinyl-1- (2,3-époxypropropoxy) benzene.

    On dissout sous agitation et atmosphère d'azote 0,71 g de NaH au 60% (0,0177 mole) dans 15 ml de dimethylformamide on ajoute lentement (pendant 30 minutes) 4,45 g (0,0169 mole) de 4-benzyloxy-3-méthylsulfinylphénol (préparé selon le procédé décrit dans US 4,396,629) dans 35 ml de dimethylformamide et après, 4,40 g (0,0169 mole) de S(+)glycildylnosilate dans 10 ml de dimethylformamide. Après l'introduction du dernier réactif le mélange est laissé réagir à température ambiante pendant 3 heures. On ajoute de l'eau, on extrait à l'acétate d'éthyle et on évapore le solvant. On purifie le brut de réaction par flash-chromatographie en eluant par un mélange CH2Cl2:MeOH = 97/3. [α]365nm = - 14,3°; [α]436nm = -3,9° (C=1% en CH3OH, t = 20°C). On obtient le composé du titre.0.71 g of 60% NaH (0.0177 mole) is dissolved in stirring under a nitrogen atmosphere in 15 ml of dimethylformamide, 4.45 g (0.0169 mole) of 4- are added slowly (over 30 minutes) benzyloxy-3-methylsulfinylphenol (prepared according to the method described in US 4,396,629) in 35 ml of dimethylformamide and thereafter 4.40 g (0.0169 mol) of S (+) glycildylnosilate in 10 ml of dimethylformamide. After the introduction of the last reagent, the mixture is left to react at room temperature for 3 hours. Add water, extract with ethyl acetate and evaporate the solvent. The crude reaction product is purified by flash chromatography, eluting with a CH 2 Cl2 mixture: MeOH = 97/3. [α] 365nm = - 14.3 °; [α] 436nm = -3.9 ° (C = 1% in CH 3 OH, t = 20 ° C). The title compound is obtained.

    Le produit ainsi obtenu est soumis à une analyse HPLC aux conditions suivantes :

    • phase stationnaire chirale :CHIRALCEL OD-H
    • phase mobile : hexane/éthanol = 80/20 (0.5 ml/min).
    The product thus obtained is subjected to an HPLC analysis under the following conditions:
    • chiral stationary phase: CHIRALCEL OD-H
    • mobile phase: hexane / ethanol = 80/20 (0.5 ml / min).

    On observe deux pics et TR1 = 20,780 min. et TR2 =23.900 min. correspondant aux diastéréoisomères ayant différente configuration à l'atome de soufre.Two peaks are observed and TR 1 = 20.780 min. and TR 2 = 23,900 min. corresponding to the diastereoisomers having different configuration to the sulfur atom.

    EXEMPLE 38EXAMPLE 38 38a) (2S) 3-[1-(5-éthoxycarbonylpyrid-2-yl)-4-pipéridinylamino-1-[(4-benzyloxy-3-méthylsulfinyl)-phenoxy]-2-propanol 38a) (2S) 3- [1- (5-ethoxycarbonylpyrid-2-yl) -4-piperidinylamino-1 - [(4-benzyloxy-3-methylsulfinyl) -phenoxy] -2-propanol

    On chauffe au reflux pendant une nuit 4.65 g (0.0146 mole) du produit de l'exemple 37 et 3,82 g (0.0153 mole) du produit de l'exemple 4 sous forme de base dans 60 ml d'éthanol. On évapore le solvant et on purifie le brut de réaction par flash-chromatographie en éluant par un mélange CH2Cl2/méthanol = 97/3. On obtient le produit du titre. P.f. : 109-110°C4.65 g (0.0146 mole) of the product of Example 37 and 3.82 g (0.0153 mole) of the product of Example 4 are heated overnight under reflux in the form of base in 60 ml of ethanol. The solvent is evaporated off and the reaction crude is purified by flash chromatography, eluting with a CH 2 Cl 2 / methanol = 97/3 mixture. The title product is obtained. Mp: 109-110 ° C

    Le produit ainsi obtenu est soumis à une analyse HPLC aux conditions suivantes :

    • phase stationnaire chirale : CHIRALCEL OD-H
    • phase mobile : hexane/éthanol = 65/35 - (0,6 ml/min, 660 psi)
    The product thus obtained is subjected to an HPLC analysis under the following conditions:
    • chiral stationary phase: CHIRALCEL OD-H
    • mobile phase: hexane / ethanol = 65/35 - (0.6 ml / min, 660 psi)

    On observe deux pics, TR1 = 20,687 min. et TR2 =28,327 min. correspondant aux diastéréoisomères ayant différente configuration à l'atome de soufre.Two peaks are observed, TR 1 = 20.687 min. and TR 2 = 28.327 min. corresponding to the diastereoisomers having different configuration to the sulfur atom.

    38b) (2S) 3-[1-(5-éthoxycarbonylpyrid-2-yl)-4-pipéridinylamino-1-[(4-hydroxy-3-méthylsulfinyl)-phenoxy]-2-propanol et son dichlorhydrate hydraté. 38b) (2S) 3- [1- (5-ethoxycarbonylpyrid-2-yl) -4-piperidinylamino-1 - [(4-hydroxy-3-methylsulfinyl) -phenoxy] -2-propanol and its hydrated dihydrochloride.

    Le produit obtenu dans l'exemple 38a) est traité avec 100 ml de CF3COOH à 55°C pendant 6 heures. On évapore le solvant et on ajoute de l'eau saturée en Na2CO3 et de la glace.The product obtained in Example 38a) is treated with 100 ml of CF 3 COOH at 55 ° C for 6 hours. The solvent is evaporated off and water saturated with Na 2 CO 3 and ice are added.

    On extrait avec de l'acétate d'éthyle on lave à l'eau en on évapore le solvant. Le brut de réaction est purifié par flash-chromatographie en éluant par un mélange CH2Cl2/méthanol = 9/1. On obtient le produit du titre : P. f. : 62-65°C. On prépare le dichlorhydrate hydraté à l'aide d'une solution de HCl en isopropanol. P.f. 172-174°C. [α]D = +4,0°; [α]436nm = +11,7° ; [α]546nm = +5,1 ° ; (C = 1% en méthanol). Le produit base est soumis à une analyse HPLC aux conditions suivantes :

    • phase stationnaire chirale : CHIRALCEL OD-H
    • phase mobile : isopropanol (0,4 ml/min, 1880 psi)
    Extraction is carried out with ethyl acetate, washing with water and the solvent is evaporated off. The crude reaction product is purified by flash chromatography, eluting with a CH 2 Cl 2 / methanol mixture = 9/1. The title product is obtained: P. f. : 62-65 ° C. The hydrated dihydrochloride is prepared using an HCl solution of isopropanol. Mp 172-174 ° C. [α] D = + 4.0 °; [α] 436nm = + 11.7 °; [α] 546nm = +5.1 °; (C = 1% in methanol). The base product is subjected to an HPLC analysis under the following conditions:
    • chiral stationary phase: CHIRALCEL OD-H
    • mobile phase: isopropanol (0.4 ml / min, 1880 psi)

    On observe deux pics, TR1 = 11,900 min. et TR2 =13,713 min. correspondant aux diastéréoisomères ayant différente configuration à l'atome de soufre.Two peaks are observed, TR 1 = 11,900 min. and TR 2 = 13.713 min. corresponding to the diastereoisomers having different configuration to the sulfur atom.

    38C) Séparation des diastéréoisomères du 38b) 38C) Separation of the diastereoisomers of 38b)

    Le produit issu de l'exemple précédente a été soumis à une HPLC chirale préparative pour la séparation des diastéréoisomères dans les conditions suivantes :

  • Appareil : PROCHROM LC 50 à compression dynamique axiale. Diamètre de la colonne 50 mm.
       Longueur de la phase stationnaire 30 cm
  • Phase stationnaire : CHIRALCEL OD 390 g de phase ciralcel OD sont mis en suspension dans 200 ml de propanol et sont comprimés à 20 bars.
  • Phase mobile : isohexane/éthanol (91/ 9) + CF3COOH 0,1% + triéthylamine 0,1%.
    • The product from the previous example was subjected to a preparative chiral HPLC for the separation of the diastereoisomers under the following conditions:
  • Device : PROCHROM LC 50 with axial dynamic compression. Column diameter 50 mm.
    Length of stationary phase 30 cm
  • Stationary phase : CHIRALCEL OD 390 g of ciralcel OD phase are suspended in 200 ml of propanol and are compressed to 20 bars.
  • Mobile phase: isohexane / ethanol (91/9) + CF 3 COOH 0.1% + triethylamine 0.1%.

    • On sépare deux produits qui, après évaporation de la phase mobile, présentent un fort excès de poids en raison de la formation de sels. Ces sels ont été éliminés par purification sur phase inverse dans les conditions suivantes :

  • Appareil : PROCHROM LC 50
  • Phase stationnaire : KROMASIL C18 100Å 10µm. 380 g de phase stationnaire sont mis en suspension dans 560 ml de méthanol et sont comprimés à 40 bars.
  • Phase mobile : Eluant A : H2O + CF3COOH 0,1% / Eluant B : CH3CN/H2O = 90/10 + CF3COOH 0,8%.
    • Two products are separated which, after evaporation of the mobile phase, present a strong excess of weight due to the formation of salts. These salts were eliminated by purification on reverse phase under the following conditions:
  • Device : PROCHROM LC 50
  • Stationary phase : KROMASIL C18 100Å 10µm. 380 g of stationary phase are suspended in 560 ml of methanol and are compressed to 40 bars.
  • Mobile phase: Eluent A: H 2 O + CF 3 COOH 0.1% / Eluent B: CH 3 CN / H 2 O = 90/10 + CF 3 COOH 0.8%.

    • Gradient d'élution : Elution gradient :

    t (en min)t (in min) %A%AT %B% B 00 9090 1010 55 9090 1010 5050 6767 3333 6060 6767 3333

    Les deux produits purifiés ont été analysés par HPLC sur chirale aux condition suivantes :

    • phase stationnaire chirale :CHIRALCEL OD
    • phase mobile: isohexane/éthanol = 85/15 + CF3COOH 0,1% + triéthylamine 0,1%.
    The two purified products were analyzed by HPLC on a chiral under the following conditions:
    • chiral stationary phase: CHIRALCEL OD
    • mobile phase: isohexane / ethanol = 85/15 + CF 3 COOH 0.1% + triethylamine 0.1%.

    Ces deux produits, correspondant aux diastéréoisomères ayant différente configuration à l'atome de soufre présentent des temps de rétention relative respectivement de TRR1 = 1 et TRR2 = 1,12. La spectrométrie de masse confirme que les deux produits obtenus ont la même masse, à savoir MH+= 478 et que leur fragmentation caractéristique est la même.These two products, corresponding to the diastereoisomers having different configurations to the sulfur atom, have relative retention times of TRR 1 = 1 and TRR 2 = 1.12 respectively. Mass spectrometry confirms that the two products obtained have the same mass, namely MH + = 478 and that their characteristic fragmentation is the same.

    EXEMPLE 39EXAMPLE 39 4-hydroxy-3-méthylcarbonyl-1-(2,3-époxypropoxy) benzène4-hydroxy-3-methylcarbonyl-1- (2,3-epoxypropoxy) benzene

    On chauffe au reflux pendant 8 heures une solution contenant 3,00 g (0,020 mole) de 2,5-dihydroxyacétophenone, 3,37 ml (0,040 mole) de épibromhydrine et 5,06 g (0,040 mole) de K2CO3 dans 30 ml de acétone. On évapore le solvant, on ajoute 20 ml d'une solution saturée en NaH2PO4, 120 ml d'eau et on extrait à l'acétate d'éthyle. A solution containing 3.00 g (0.020 mole) of 2,5-dihydroxyacetophenone, 3.37 ml (0.040 mole) of epibromhydrin and 5.06 g (0.040 mole) of K 2 CO 3 in 30 ml of acetone. The solvent is evaporated off, 20 ml of a saturated NaH 2 PO 4 solution , 120 ml of water are added and the mixture is extracted with ethyl acetate.

    On évapore le solvant et on purifie le brut de réaction par chromotographie en éluant par un mélange de CH2Cl2 et acétate d'éthyle en rapport variable entre 100/0 et 95/5. On obtient le produit du titre. P.f. : 83-35°C.The solvent is evaporated off and the reaction crude is purified by chromotography, eluting with a mixture of CH 2 Cl 2 and ethyl acetate in variable ratio between 100/0 and 95/5. The title product is obtained. Mp: 83-35 ° C.

    EXEMPLE 40EXAMPLE 40 4-benzyloxy-3-méthylcarbonyl-1-(2,3-époxypropoxy)-benzène4-benzyloxy-3-methylcarbonyl-1- (2,3-epoxypropoxy) -benzene

    On chauffe au reflux pendant 6 heures sous azote une solution contenant 1 g (0,0048 mole) du produit de l'exemple 39, 0,856 ml (0,0072 mole) de benzyl-bromure et 0,924 g (0,0072 mole) de K2CO3 dans 12 ml d'acétone. On ajoute encore 0,5 ml (0.0042 mole) de benzyl-bromure et on chauffe encore pendant 7 heures. On verse dans l'eau, on extrait à l'acétate d'éthyle et on évapore le solvant. Le brut de réaction est purifié par chromatographie, en éluant par un mélange héxane/acétone = 8/2. On obtient le produit du titre. P.f. : 45-48°C.A solution containing 1 g (0.0048 mole) of the product of Example 39, 0.856 ml (0.0072 mole) of benzyl bromide and 0.924 g (0.0072 mole) of is heated under reflux for 6 hours under nitrogen. K 2 CO 3 in 12 ml of acetone. Another 0.5 ml (0.0042 mole) of benzyl bromide is added and the mixture is further heated for 7 hours. It is poured into water, extracted with ethyl acetate and the solvent is evaporated. The crude reaction product is purified by chromatography, eluting with a hexane / acetone mixture = 8/2. The title product is obtained. Mp: 45-48 ° C.

    EXEMPLE 41EXAMPLE 41 3-[1-(5-éthoxycarbonylpyrid-2-yl)-4-pipéridinylamino]-1-[(4-hydroxy-3-méthylcarbonyl)-phenoxy]-2-propanol3- [1- (5-éthoxycarbonylpyrid-2-yl) -4-piperidinylamino] -1 - [(4-hydroxy-3-methylcarbonyl) -phenoxy] -2-propanol

    En opérant comme décrit dans l'exemple 9 mais en utilisant le produit de l'exemple 40 au lieu du 4-benzyloxy-1-(2,3-époxypropoxy)-benzène on obtient le produit du titre. P.f.: 105-108°C.By operating as described in Example 9 but using the product of Example 40 instead of 4-benzyloxy-1- (2,3-epoxypropoxy) -benzene, the title product. M.p .: 105-108 ° C.

    EXEMPLE 42EXAMPLE 42 (1-méthylcarbonyl-3-bromo-4-benzyloxy)-benzène(1-methylcarbonyl-3-bromo-4-benzyloxy) -benzene

    On chauffe au reflux pendant 4 heures une solution contenant 0,92 g (0,428 mole) de (2-bromo-4-méthylcarbonyl)-phénol, 51 ml (0,428 mole) de benzyl-bromure, 6,4 gr de NaI (0,043 mole) et 89,0 gr (0,642) de K2CO3 dans 1,5 1 d'acétone. On filtre, on évapore le solvant on ajoute de l'acétate d'éthyle et on lave à l'eau. On évapore le solvant et on obtient le produit du titre. P.f. : 117-119 °C.A solution containing 0.92 g (0.428 mole) of (2-bromo-4-methylcarbonyl) -phenol, 51 ml (0.428 mole) of benzyl bromide, 6.4 g of NaI (0.043) is heated at reflux for 4 hours. mole) and 89.0 gr (0.642) of K 2 CO 3 in 1.5 1 of acetone. It is filtered, the solvent is evaporated off, ethyl acetate is added and it is washed with water. The solvent is evaporated off and the title product is obtained. Mp: 117-119 ° C.

    EXEMPLE 43EXAMPLE 43 (3-bromo-4-benzyloxy-1-acétoxy)-benzène(3-bromo-4-benzyloxy-1-acetoxy) -benzene

    On chauffe au reflux pendant 24 heures une solution contenant 93 gr (0,3 mole) du produit de l'exemple 42 et 259 g (1,05 mole) de acide-3-chloro perbenzoique (cône. 70%) dans 2 1 de CH2Cl2. On évapore le solvant, on ajoute de l'acétate d'éthyle et on lave avec une solution de Na2S2O5. On filtre et on évapore le solvant. On obtient le composé du titre. P.f. : 69-71°C.A solution containing 93 gr (0.3 mole) of the product of Example 42 and 259 g (1.05 mole) of 3-chloro perbenzoic acid (cone. 70%) in 2 1 is heated at reflux for 24 hours. of CH 2 Cl 2 . The solvent is evaporated off, ethyl acetate is added and the mixture is washed with a solution of Na 2 S 2 O 5 . It is filtered and the solvent is evaporated. The title compound is obtained. Mp: 69-71 ° C.

    EXEMPLE 44EXAMPLE 44 [4-benzyloxy-3-(2-furyl)]phénol[4-benzyloxy-3- (2-furyl)] phenol

    On chauffe à 90°C pendant 5 heures sous atmosphère d'Argon une solution de 180 ml de dioxane contenant 13 g (0,0406 mole) du produit de l'exemple 43, 5 g (0,0447 mole) de l'acide 2-furanboronique, 1,6 g de Tetrakis (tryphénylphosphine)-Palladium et 38,3 g (0,1215 mole) de fluorure de Tetrabutylammonium. On ajoute 1 1 d'éther éthylique et on lave à l'eau.Heated at 90 ° C for 5 hours under an Argon atmosphere a solution of 180 ml of dioxane containing 13 g (0.0406 mole) of the product of Example 43, 5 g (0.0447 mole) of 2-furanboronic acid, 1.6 g of Tetrakis (tryphenylphosphine) -Palladium and 38.3 g (0.1215 mole) of Tetrabutylammonium fluoride. We add 1 1 ethyl ether and washed with water.

    On filtre et on évapore le solvant. Le brut de réaction est purifié par chromatographie (éluant cyclohexane/éthyle acétate = 8/29). On obtient le composé du titre. P.f. : 112-115°C.It is filtered and the solvent is evaporated. The crude reaction product is purified by chromatography (eluent cyclohexane / ethyl acetate = 8/29). We obtain the compound of title. Mp Mp: 112-115 ° C.

    EXEMPLE 45EXAMPLE 45 [4-benzyloxy-3-fur-2-yl-1-(2,3-époxypropoxy)]-benzène[4-benzyloxy-3-fur-2-yl-1- (2,3-epoxypropoxy)] - benzene

    On laisse sous agitation à température ambiante pendant 15 minutes 8,3 g (0,031 mole) du produit de l'étape précédente avec 6,5 g (0,046 mole) de K2CO3 dans 60 ml de dimethylformamide. Après 15 minutes on ajoute 5,3 ml (0,062) de epibromhydrine et on chauffe à 70 °C pendant 6 heures. On verse dans un mélange d'eau et de glace et on extrait à l'acétate d'éthyle. On filtre et on évapore le solvant. On purifie le brut de réaction par chromatographie en éluant par un mélange cyclohéxane/éthyl acétate = 85/15 et par la suite cyclohéxane/éthylacétate = 9/1. On obtient le produit du titre. P.f: 62-64°C.8.3 g (0.031 mole) of the product from the preceding step are left stirring at room temperature for 15 minutes with 6.5 g (0.046 mole) of K 2 CO 3 in 60 ml of dimethylformamide. After 15 minutes, 5.3 ml (0.062) of epibromhydrin is added and the mixture is heated at 70 ° C. for 6 hours. It is poured into a mixture of water and ice and extracted with ethyl acetate. It is filtered and the solvent is evaporated. The reaction crude is purified by chromatography, eluting with a cyclohexane / ethyl acetate mixture = 85/15 and then cyclohexane / ethyl acetate = 9/1. The title product is obtained. Mp: 62-64 ° C.

    EXEMPLE 46EXAMPLE 46 3-[1-(5-éthoxycarbonylpyrid-2-yl)-4-pipéridinylamino]-1-[(4-hydroxy-3-(2-furyl)-phenoxy]-2-propanol et son dichlorydrate hydraté3- [1- (5-éthoxycarbonylpyrid-2-yl) -4-piperidinylamino] -1 - [(4-hydroxy-3- (2-furyl) -phenoxy] -2-propanol and its hydrated dichlorydrate

    On opère comme décrit dans l'exemple 26 mais en utilisant le produit de l'exemple 45 au lieu du 4-benzyloxy-3-méthylsulfinyl-1-(2,3-époxypropoxy)-benzène. Le clivage du groupe benzyle est fait par hydrogénation en acétate d'éthyle. Le brut de réaction est purifié par chromatographie en éluant par uns mélange éthyle acétate/méthanol = 85/15. On prépare le chlorhydrate dans l'isopropanol. On obtient le produit du titre. P.f. : 251-253°C déc.The procedure is as described in Example 26 but using the product of Example 45 instead of 4-benzyloxy-3-methylsulfinyl-1- (2,3-epoxypropoxy) -benzene. Cleavage of the benzyl group is done by hydrogenation to ethyl acetate. The gross of reaction is purified by chromatography, eluting with an ethyl mixture acetate / methanol = 85/15. The hydrochloride is prepared in isopropanol. We get the title product. Mp : 251-253 ° C Dec.

    EXEMPLE 47EXAMPLE 47 3-bromo-4-benzyloxy-phenol3-bromo-4-benzyloxy-phenol

    On fait réagir sous agitation pendant 40 minutes à température ambiante 0,5 g (0,0155 mole) du produit de l'exemple 43 avec 18,7 ml (0,0187)de NaOH 1N dans 150 ml de méthanol. On ajoute de l'acide citrique jusqu'à pH 6 et on évapore le solvant. On ajoute de l'acétate d'éthyle, on lave à l'eau et on évapore le solvant. On obtient le composé du titre. P.f. : 61-63 °C.React with stirring for 40 minutes at room temperature 0.5 g (0.0155 mole) of the product of Example 43 with 18.7 ml (0.0187) of 1N NaOH in 150 ml of methanol. Citric acid is added to pH 6 and the solvent is evaporated. We add ethyl acetate, wash with water and evaporate the solvent. We get the composed of the title. Mp : 61-63 ° C.

    EXEMPLE 48EXAMPLE 48 3-bromo-4-benzyloxy-1-(2,3-époxypropoxy)-benzène3-bromo-4-benzyloxy-1- (2,3-epoxypropoxy) -benzene

    On chauffe à 45 °C pendant une nuit 3,5 g (0,0125 mole) du produit de l'exemple 47, 18,8 ml (0,0188 mole) de NaOH 1M et 2,2 ml (0,025 mole) de épibromhydrine dans 50 ml de dioxane. On évapore le solvant, on ajoute de l'eau, on extrait à l'acétate d'éthyle et on évapore le solvant. On purifie le brut de réaction par chromatographie (cyclohéxane/acétate d'éthyle = 8/2). On obtient le composé du titre. Heated to 45 ° C overnight 3.5 g (0.0125 mole) of the product of the example 47, 18.8 ml (0.0188 mole) of 1M NaOH and 2.2 ml (0.025 mole) of epibromhydrin in 50 ml of dioxane. The solvent is evaporated off, water is added, extraction is carried out with ethyl acetate and the solvent is evaporated. The reaction crude is purified by chromatography (cyclohexane / ethyl acetate = 8/2). The title compound is obtained.

    EXEMPLE 49EXAMPLE 49 3-[1-(5-éthoxycarbonylpyrid-2-yl)-4-pipéridinylamino]-1-[3-bromo-4-hydroxy)phenoxy]-2-propanol3- [1- (5-éthoxycarbonylpyrid-2-yl) -4-piperidinylamino] -1- [3-bromo-4-hydroxy) phenoxy] -2-propanol

    On fait réagir le produit de l'exemple 48 avec le produit de l'exemple 4 (base), selon le procédé décrit dans l'exemple 9a. Le produit issu de cette réaction est traité avec du CF3COOH à 55°C pendant 4 heures. Le brut de réaction est purifié par chromatographie (CH2Cl2/CH3OH = 93/7). On cristallise le produit dans de l'isopropanol. P.f.:123-126 °CThe product of Example 48 is reacted with the product of Example 4 (base), according to the process described in Example 9a. The product resulting from this reaction is treated with CF 3 COOH at 55 ° C for 4 hours. The crude reaction product is purified by chromatography (CH 2 Cl 2 / CH 3 OH = 93/7). The product is crystallized from isopropanol. Mp: 123-126 ° C

    EXEMPLE 50EXAMPLE 50 4-benzyloxy-3-[(N-tertbutoxycarbonyl-N-méthylsulfonyl)-amino]-1-(2,3-époxypropoxy)-benzène.4-benzyloxy-3 - [(N-tertbutoxycarbonyl-N-methylsulfonyl) amino] -1- (2,3-epoxypropoxy) benzene.

    On chauffe au reflux pendant 24 heures une solution contenant 1 g (0,0025 mole) de 4-phenylméthoxy-3-[(N-tertbutoxycarbonyl-N-methansulfonyl)-amino]-phenol (préparé selon le procédé décrit dans WO 9604233), 0,75 g (0,0029 mole) de glycidylnosilate et 1,1 g (0,008 mole de K2CO3. On filtre, on évapore le solvant et on purifie le brut de réaction par chromatographie en éluant par un mélange cyolohexane/éthyl acétate = 7/3.A solution containing 1 g (0.0025 mole) of 4-phenylmethoxy-3 - [(N-tertbutoxycarbonyl-N-methansulfonyl) -amino] -phenol (prepared according to the method described in WO 9604233) is heated at reflux for 24 hours. , 0.75 g (0.0029 mole) of glycidylnosilate and 1.1 g (0.008 mole of K 2 CO 3) The mixture is filtered, the solvent is evaporated and the reaction crude is purified by chromatography, eluting with a cyolohexane / ethyl acetate = 7/3.

    EXEMPLE 51EXAMPLE 51 51a) 3-[1-(5-éthoxycarbonylpyrid-2-yl)-4-pipéridinylamino]-1-[(4-benzyloxy-3-méthansulfonamido)-phenoxy]-2-propanol51a) 3- [1- (5-ethoxycarbonylpyrid-2-yl) -4-piperidinylamino] -1 - [(4-benzyloxy-3-methansulfonamido) -phenoxy] -2-propanol

    On fait réagir sous agitation pendant 48 heures à température ambiante 0,77 g (0,00172 mole) du produit de l'exemple 50, 0,86 g (0,0035mole) du produit de l'exemple 4 base et 0,2 g de LiClO4 dans 50 ml de acetonitrile. On chauffe à 40 °C pendant 9 heures et on arrête le réaction. On évapore le solvant et on ajoute 30 ml de CH2Cl et une solution 3N de HCl en éthyle acétate (20 ml). On chauffe pendant 4 heures à 40 °C pour évaporer le solvant. On lave à l'ammoniac et on extrait à l'acétate d'éthyle. On évapore le solvant et on purifie le brut de réaction par flash chromatographie en éluant par un mélange CH2Cl2/CH3OH = 9/1. On obtient le produit du titre. P.f.: 112-114°CReacting with stirring for 48 hours at room temperature 0.77 g (0.00172 mole) of the product of Example 50, 0.86 g (0.0035mole) of the product of Example 4 base and 0.2 g of LiClO 4 in 50 ml of acetonitrile. The mixture is heated at 40 ° C for 9 hours and the reaction is stopped. The solvent is evaporated off and 30 ml of CH 2 Cl and a 3N solution of HCl in ethyl acetate (20 ml) are added. The mixture is heated for 4 hours at 40 ° C. to evaporate the solvent. Washed with ammonia and extracted with ethyl acetate. The solvent is evaporated off and the reaction crude is purified by flash chromatography, eluting with a CH 2 Cl 2 / CH 3 OH = 9/1 mixture. The title product is obtained. Mp: 112-114 ° C

    51b) 3-[1-(5-éthoxycarbonylpyrid-2yl)-4-pipéridinylamino]-1-[-4-hydroxy-3-méthansulfonamido)-phenoxy]-2-propanol 51b) 3- [1- (5-ethoxycarbonylpyrid-2yl) -4-piperidinylamino] -1 - [- 4-hydroxy-3-methansulfonamido) -phenoxy] -2-propanol

    On hydrogène le produit de l'exemple 51a selon le procédé décrit dans l'exemple 9b, en opérant à une pression variable entre la pression ambiante et 50 psi. Le brut de réaction est purifié par flash-chromatographie (CH2Cl/CH3OH = 9/1). On obtient le produit du titre. P.f. : 77-80 °C.The product of Example 51a is hydrogenated according to the process described in Example 9b, operating at a pressure that varies between ambient pressure and 50 psi. The crude reaction product is purified by flash chromatography (CH 2 Cl / CH 3 OH = 9/1). The title product is obtained. Mp: 77-80 ° C.

    EXEMPLE 52EXAMPLE 52 4-acétylamino-1-(5-chloropyrid-2-yl)-pipéridine4-acetylamino-1- (5-chloropyrid-2-yl) -piperidine

    On chauffe au reflux pendant 24 heures 6,7 g (0,035 mole) de 2-bromo-5-chloropyridine 4,97 g (0,035 mole) de 4 acétylamino-piperidine et 4,83 g (0,035 mole) de K2CO3 dans 50 ml alcool amylique. On évapore le solvant, on ajoute de l'eau et on extrait au CH2Cl2.On obtient le produit du titre. P.f. : 196-198 °C.Heated at reflux for 24 hours 6.7 g (0.035 mole) of 2-bromo-5-chloropyridine 4.97 g (0.035 mole) of 4 acetylamino-piperidine and 4.83 g (0.035 mole) of K 2 CO 3 in 50 ml amyl alcohol. The solvent is evaporated off, water is added and the mixture is extracted with CH 2 Cl 2. The title product is obtained. Mp: 196-198 ° C.

    EXEMPLE 53EXAMPLE 53 4-amino-1-(5-chloropyrid-2-yl)-pipéridine et son dichlorohydrate4-amino-1- (5-chloropyrid-2-yl) -piperidine and its dihydrochloride

    On chauffe au reflux pendant 5 heures 5,5 g (0.022 mole) du produit de l'exemple 52 dans 25 ml de HCl 6N. On évapore le solvant, on ajoute 50 ml d'eau et une solution de NaOH jusqu'à pH basique. On extrait au CH2Cl2, on évapore le solvant on prépare le chlorohydrate dans de l'isopropanol, et on cristallise dans du méthanol. On obtient le produit du titre. P.f. : 295 °C déc.5.5 g (0.022 mol) of the product of Example 52 in 25 ml of 6N HCl are heated to reflux for 5 hours. The solvent is evaporated off, 50 ml of water and an NaOH solution are added to basic pH. Extracted with CH 2 Cl 2 , the solvent is evaporated, the hydrochloride is prepared in isopropanol, and crystallized from methanol. The title product is obtained. Mp: 295 ° C dec.

    EXEMPLE 54EXAMPLE 54 3-[1-(5-chloropyrid-2-yl)-4-pipéridinylamino]-1-(4-hydroxyphénoxy)-2-propanol3- [1- (5-chloropyrid-2-yl) -4-piperidinylamino] -1- (4-hydroxyphenoxy) -2-propanol

    On opère comme décrit dans l'exemple 12 mais en utilisant le produit de l'exemple 53 (base) au lieu du produit de l'exemple 6. Après le traitement avec CF3COOH on évapore, on ajoute de l'éthyle acétate et on lave à l'aide d'une solution de NaH2PO4 jusqu'à pH 5. On évapore le solvant et on purifie le brut de réaction par flash-chromatographie en eluant par un mélange CH2Cl2/méthanol = 9/1. On obtient le produit du titre. P.f : 148-150 °C.The procedure is as described in Example 12 but using the product of Example 53 (base) instead of the product of Example 6. After the treatment with CF 3 COOH, the mixture is evaporated, ethyl acetate is added and washed with a NaH 2 PO 4 solution to pH 5. The solvent is evaporated and the reaction crude is purified by flash chromatography, eluting with a CH 2 Cl 2 / methanol = 9 / mixture. 1. The title product is obtained. Mp: 148-150 ° C.

    EXEMPLE 55EXAMPLE 55 2-chloro-6-éthoxycarbonyl-pyridine2-chloro-6-ethoxycarbonyl-pyridine

    On chauffe au reflux pendant 8 heures 14,1 g (0,0895 mole) de 2-chloro-6-hydroxycarbonylpyridine dans 133 ml d'une solution de HCl en éthanol. On évapore le solvant, on ajoute de l'acétate d'éthyle et on lave à l'aide d'une solution de bicarbonate. On évapore encore le solvant et on purifie le brut de réaction par flash-chromatographie (cyclohéxane/acétate d'éthyle =7/3). On obtient le produit du titre.14.1 g (0.0895 mol) of 2-chloro-6-hydroxycarbonylpyridine are heated at reflux for 8 hours. in 133 ml of an ethanol HCl solution. We evaporate the solvent, ethyl acetate is added and washed with a bicarbonate solution. The solvent is further evaporated and the reaction crude is purified by flash chromatography (cyclohexane / ethyl acetate = 7/3). The title product is obtained.

    EXEMPLE 56EXAMPLE 56 4-tert-butoxycarbonylamino-1-(6-éthoxycarbonylpyrid-2-yl)-pipéridine4- tert -butoxycarbonylamino-1- (6-ethoxycarbonylpyrid-2-yl) -piperidine

    On chauffe à 80 °C pendant 24 heures une solution contenant 1,17 g (0,0063 mole) du produit de l'exemple 55, 1,27 g (0,0063 mole) du produit de la préparation 1, 0,9 ml de triethylamine et du NaI dans 34,2 ml de dimethylformamide. On verse dans l'eau, on extrait à l'acétate d'éthyle et on évapore le solvant. Le brut de réaction est purifié par flash-chromatographie en éluant par un mélange cyclohéxane/acétate d'éthyle = 7/3.A solution containing 1.17 g (0.0063) is heated at 80 ° C. for 24 hours. mole) of the product of Example 55, 1.27 g (0.0063 mole) of the product of preparation 1, 0.9 ml of triethylamine and NaI in 34.2 ml of dimethylformamide. We pour into water, extraction with ethyl acetate and the solvent is evaporated. The reaction crude is purified by flash chromatography, eluting with a cyclohexane / ethyl acetate mixture = 7/3.

    EXEMPLE 57EXAMPLE 57 4- amino-1-(6-éthoxycarbonylpyrid-2-yl)-pipéridine et son chlorohydrate4- amino-1- (6-ethoxycarbonylpyrid-2-yl) -piperidine and its hydrochloride

    On chauffe au reflux pendant 8 heures 0,99 g (0,0025 mole) du produit de l'exemple 56 dans 6 ml d'acétate d'éthyle et 6 ml d'une solution de HCl en acétate d'éthyle. On filtre, on lave à l'acétone, on ajoute de l'ammoniac et on extrait à l'acétate d'éthyle. Le brut de réaction est purifié par chromatographie en éluant par un mélange CH3OH/NH4OH = 100/1. On obtient le produit du titre.0.99 g (0.0025 mol) of the product of Example 56 is heated under reflux for 8 hours in 6 ml of ethyl acetate and 6 ml of a solution of HCl in ethyl acetate. Filter, wash with acetone, add ammonia and extract with ethyl acetate. The crude reaction product is purified by chromatography, eluting with a CH 3 OH / NH 4 OH mixture = 100/1. The title product is obtained.

    EXEMPLE 58EXAMPLE 58 58a/ 3-[1-(6-éthoxycarbonyl-pyrid-2-yl)-4-pipéridinylamino]-1-(4-benzyloxy phénoxy)-2-propanol 58a / 3- [1- (6-ethoxycarbonyl-pyrid-2-yl) -4-piperidinylamino] -1- (4-benzyloxy phenoxy) -2-propanol

    On chauffe au reflux pendant une nuit 0,3 g (0,0012 mole) du produit de l'exemple 57 base, 0,292 g (0,00114 mole) de 4-benzyloxy-1-(2,3-époxypropoxy)benzène dans 15 ml d'éthanol. On évapore sous pression réduite et on purifie le brut de réaction par chromatographie en éluant par un mélange CH3OH/acétate d'éthyle 9/1.0.3 g (0.0012 mole) of the product is heated at reflux overnight. Example 57 base, 0.292 g (0.00114 mole) of 4-benzyloxy-1- (2,3-epoxypropoxy) benzene in 15 ml of ethanol. It is evaporated under reduced pressure and purifies the reaction crude by chromatography, eluting with a mixture CH3OH / ethyl acetate 9/1.

    58b/ 3-[1-(6-éthoxycarbonyl-pyrid-2-yl)-4-pipéridinylamino]-1-(4-hydroxyphénoxy)-2-propanol 58b / 3- [1- (6-ethoxycarbonyl-pyrid-2-yl) -4-piperidinylamino] -1- (4-hydroxyphenoxy) -2-propanol

    On opérant comme décrit dans l'exemple 9b on obtient le composé du titre. P.f. : 200°C-201°C.Operating as described in Example 9b, the title compound is obtained. Mp : 200 ° C-201 ° C.

    EXEMPLE 59EXAMPLE 59 59a) (2S) 3-[5-aminocarbonyl-pyrid-2-yl)-4-pipéridinylamino]-1-(4-benzyloxy-3-méthylsulfinyl-phénoxy)-2-propanol 59a) (2S) 3- [5-aminocarbonyl-pyrid-2-yl) -4-piperidinylamino] -1- (4-benzyloxy-3-methylsulfinyl-phenoxy) -2-propanol

    On chauffe au reflux, sous atmosphère d'azote pendant 6 heures 1 g (0,00314 mole) du produit de l'exemple 37 et 0,83 g (0,00377 mole) du produit de l'exemple 2 sous forme de base. On évapore le solvant et on purifie le brut de réaction par chromatographie en éluant par un mélange CH2Cl2/méthanol/NH4OH = 90/10/1. On obtient le produit du titre. P.f. :143-147°C.Is heated under reflux, under a nitrogen atmosphere for 6 hours 1 g (0.00314 mole) of the product of Example 37 and 0.83 g (0.00377 mole) of the product of Example 2 in the form of the base . The solvent is evaporated off and the reaction crude is purified by chromatography, eluting with a CH 2 Cl 2 / methanol / NH 4 OH = 90/10/1 mixture. The title product is obtained. Mp: 143-147 ° C.

    Le produit ainsi obtenu est soumis à une analyse HPLC aux conditions suivantes:

    • phase stationnaire chirale :CHIRALCEL OD-H
    • phase mobile : héxane/éthanol = 20/80 - (0,4 ml/min) On observe deux pics, TR1 = 17,040 min., TR2 = 19,827 min. correspondant aux diastéréoisomères ayant different configuration à l'atome de soufre.
    The product thus obtained is subjected to an HPLC analysis under the following conditions:
    • chiral stationary phase: CHIRALCEL OD-H
    • mobile phase: hexane / ethanol = 20/80 - (0.4 ml / min) Two peaks are observed, TR 1 = 17.040 min., TR 2 = 19.827 min. corresponding to the diastereoisomers having different configuration to the sulfur atom.

    59b) (2S) 3-[5-aminocarbonyl-pyrid-2-yl)-4-pipéridinylamino]-1-(4-hydroxy-3-méthylsulfinyl-phénoxy)-2-propanol 59b) (2S) 3- [5-aminocarbonyl-pyrid-2-yl) -4-piperidinylamino] -1- (4-hydroxy-3-methylsulfinyl-phenoxy) -2-propanol

    On travaille comme décrit dans l'exemple 38b) mais en utilisant le produit da l'exemple 59a) en lieu du produit de l'exemple 38a). Le brut de réaction est purifié une première fois par chromatographie en éluant par un mélange CH2Cl2/méthanol/NH4OH = 85/15/1,5 puis 80/20/2. On conduit après une deuxième chromatographie en éluant par un mélange éthyle acétate/méthanol = 80/20 suivi par un mélange CH2Cl2/méthanol/NH4OH = 85/15/1,5 puis 80/20/2. On obtient le produit du titre. P.f. : 74°C.The procedure is as described in Example 38b) but using the product of Example 59a) instead of the product of Example 38a). The crude reaction product is purified a first time by chromatography, eluting with a CH 2 Cl 2 / methanol / NH 4 OH mixture = 85/15 / 1.5 then 80/20/2. The reaction is carried out after a second chromatography, eluting with an ethyl acetate / methanol mixture = 80/20 followed by a CH 2 Cl 2 / methanol / NH 4 OH mixture = 85/15 / 1.5 then 80/20/2. The title product is obtained. Mp: 74 ° C.

    Le produit ainsi obtenu est soumis à une analyse HPLC aux conditions suivantes:

    • phase stationnaire chirale :CHIRALCEL OD-H
    • phase mobile : héxane/éthanol = 65/35 - (0,6 ml/min) On observe deux pics, TR1 = 13,900 min., TR2 = 18,233 min. correspondant aux diastéréoisomères ayant different configuration à l'atome de soufre.
    The product thus obtained is subjected to an HPLC analysis under the following conditions:
    • chiral stationary phase: CHIRALCEL OD-H
    • mobile phase: hexane / ethanol = 65/35 - (0.6 ml / min) Two peaks are observed, TR 1 = 13,900 min., TR 2 = 18,233 min. corresponding to the diastereoisomers having different configuration to the sulfur atom.

    EXEMPLE 60EXAMPLE 60 3-[1-(5-hydroxycarbonyl-pyrid-2-yl)-4-pipéridinylamino]-1-[(4-hydroxy-3-méthylsulfinyl)-phenoxy]-2-propanol3- [1- (5-hydroxycarbonyl-pyrid-2-yl) -4-piperidinylamino] -1 - [(4-hydroxy-3-methylsulfinyl) phenoxy] -2-propanol

    On mélange à la température ambiante 0,48g (0,001 mole) du produit de l'exemple 26b 2,51 ml de NaOH 1N (0,0025 mole), 2,5 ml d'eau et 2,5 ml d'éthanol. Après 24 heures on évapore l'éthanol et on ajoute 0,144 ml de acide acétique (d=1,049, 0,0025 mole). On observe la formation d'un huile. On élimine l'eau et on ajoute 10 ml d'éthanol. On évapore le solvant et on ajoute encore de l'éthanol. On répète cette opération plusieurs fois. On obtient le produit du titre. P.f. : 215-217 déc.0.48 g (0.001 mole) of the product is mixed at ambient temperature. Example 26b 2.51 ml of 1N NaOH (0.0025 mole), 2.5 ml of water and 2.5 ml of ethanol. After 24 hours, the ethanol is evaporated off and 0.144 ml of acetic acid is added (d = 1.049, 0.0025 mole). An oil formation is observed. Remove the water and add 10 ml ethanol. The solvent is evaporated off and additional ethanol is added. We repeat this operation several times. The title product is obtained. Mp : 215-217 Dec

    EXEMPLE 61EXAMPLE 61 (3-acétylamino-4-benzyloxy-1-acétoxy)-benzène(3-acetylamino-4-benzyloxy-1-acetoxy) -benzene

    On dissout sous agitation 2 g (0,0077 mole) de (3-amino-4-benzyloxy-1-acétoxy)-benzène (préparé selon le procédé décrit en Synt. Commun. 22 ; 20 ; 1992 ; 2877-2882) dans 150 ml de CH2Cl2 on ajoute 1,3 ml de triéthylamine (0,0093 mole) et ensuite 0,8 ml de anydride acétique (0,0085 mole). Après une nuit on chauffe au reflux pendant 4 heures. On lave à l'eau, on filtre et on évapore le solvant. On ajoute du cyclohéxane et on filtre. On obtient le produit du titre. P.f. :105-107°C.2 g (0.0077 mol) of (3-amino-4-benzyloxy-1-acetoxy) -benzene (prepared according to the method described in Commun. Synt. 22; 20; 1992; 2877-2882) are dissolved with stirring 150 ml of CH 2 Cl 2 is added 1.3 ml of triethylamine (0.0093 mole) and then 0.8 ml of acetic anydride (0.0085 mole). After one night heating at reflux for 4 hours. Wash with water, filter and evaporate the solvent. Cyclohexane is added and filtered. The title product is obtained. Mp: 105-107 ° C.

    EXEMPLE 62EXAMPLE 62 3-acétylamino-4-benzyloxy-phénol3-acetylamino-4-benzyloxy-phenol

    On dissout 3 g (0,010 mole) du produit de l'étape précédente dans 120 ml de méthanol et 30 ml d'eau. On ajoute 12 ml de NaOH 1N (0,012 mole) et on laisse sous agitation à température ambiante pendant 30 minutes. On ajoute de l'acide citrique jusqu'à pH = 6, on évapore le solvant, on ajoute de l'éthyle acétate et on lave à l'eau. On filtre et on sèche. On obtient le produit du titre.3 g (0.010 mole) of the product from the previous step are dissolved in 120 ml of methanol and 30 ml of water. 12 ml of 1N NaOH (0.012 mol) are added and the mixture is left under stirring at room temperature for 30 minutes. Citric acid is added until pH = 6, the solvent is evaporated off, ethyl acetate is added and the mixture is washed with water. We filter and dry. The title product is obtained.

    EXEMPLE 63EXAMPLE 63 3-acétylamino-4-benzyloxy-1-(2,3-époxypropoxy)-benzène3-acetylamino-4-benzyloxy-1- (2,3-epoxypropoxy) -benzene

    On mélange sous agitation à température ambiante pendant 15 minutes 0,5 g (0,0019 mole) du produit de l'exemple 62 avec 0,4 g de K2CO3 ( 0,0029) dans 5 ml de diméthylformamide. Après 15 minutes on ajoute 0,32 ml (0,0038 mole) de épibromhydrine et on laisse réagir pendant une nuit. On verse dans l'eau, on extrait à l'éthyle acétate, on sèche et on filtre. Le brut de réaction est purifié par chromatographie en éluant par un mélange cyclohéxane/éthyle acétate = 6/4. On obtient le produit du titre. 0.5 g (0.0019 mole) of the product of Example 62 is mixed with stirring at room temperature for 15 minutes with 0.4 g of K 2 CO 3 (0.0029) in 5 ml of dimethylformamide. After 15 minutes, 0.32 ml (0.0038 mole) of epibromhydrin is added and the mixture is left to react overnight. Pour into water, extract with ethyl acetate, dry and filter. The crude reaction product is purified by chromatography, eluting with a cyclohexane / ethyl acetate mixture = 6/4. The title product is obtained.

    EXEMPLE 64EXAMPLE 64 64a) 3-[1-(5-éthoxycarbonyl-pyrid-2-yl)-4-pipéridinylamino]-1-[(3-acétylamino-4-benzyloxy)-phenoxy]-2-propanol 64a) 3- [1- (5-ethoxycarbonyl-pyrid-2-yl) -4-piperidinylamino] -1 - [(3-acetylamino-4-benzyloxy) -phenoxy] -2-propanol

    64a) On chauffe au reflux pendant une nuit 0,22 g (0.0007 mole) du produit de l'exemple 63 avec 0,175 g (0,0007 mole) du produit de l'exemple 4 sous forme de base dans 10 ml d'éthanol. On évapore le solvant et on purifie le brut par flash-chromatographie en éluant par méthanol. On évapore le solvant et on obtient le produit du titre. P.f. : 124-126°C64a) 0.22 g (0.0007 mole) of the product is heated at reflux overnight. Example 63 with 0.175 g (0.0007 mole) of the product of Example 4 in the form of the base in 10 ml of ethanol. The solvent is evaporated off and the crude product is purified by flash chromatography eluting with methanol. The solvent is evaporated and the product is obtained of the title. Mp : 124-126 ° C

    64b) 3-[1-(5-éthoxycarbonyl-pyrid-2-yl)-4-pipéridinylamino]-1-[(3-acétylamino-4-hydroxy)-phenoxy]-2-propanol64b) 3- [1- (5-ethoxycarbonyl-pyrid-2-yl) -4-piperidinylamino] -1 - [(3- acetylamino-4-hydroxy) -phenoxy] -2-propanol

    On hydrogène le produit de l'exemple 64a selon le procédé décrit dans l'exemple 9b. On obtient le produit du titre. P.f. : 103-105°C.The product of Example 64a is hydrogenated according to the process described in the example. 9b. The title product is obtained. Mp : 103-105 ° C.

    EXEMPLE 65EXAMPLE 65 (3-méthylsulfonyl-4-benzyloxy-1-phenylcarbonyloxy)-benzène(3-methylsulfonyl-4-benzyloxy-1-phenylcarbonyloxy) -benzene

    On dissout 3,26 g (0,0089 mole) de (3-méthylsulfinyl-4-benzyloxy-1-phénylcarbonyloxy)-benzène dans 30 ml d'acétone et 5 ml de méthanol et on ajoute, à une température comprise entre 5 et 10 °C, 2,86 g de monopéroxyphtalate de magnésium (MMPP) (pureté = 80%, 0,0046 mole) dissout en 20 ml de méthanol. Après 3,5 heures on ajoute encore 0,3 g (0,00048 mole) de MMPP dans 1 ml de méthanol. On laisse réagir à température ambiante pendant une nuit. On ajoute 50 ml d'eau, 5 ml d'une solution saturée en NaHCO3 et on extrait à l'acétate d'éthyle. On évapore le solvant et on obtient le produit du titre. P.f. : 142-145°C.3.26 g (0.0089 mol) of (3-methylsulfinyl-4-benzyloxy-1-phenylcarbonyloxy) -benzene are dissolved in 30 ml of acetone and 5 ml of methanol and added, at a temperature between 5 and 10 ° C, 2.86 g of magnesium monoperoxyphthalate (MMPP) (purity = 80%, 0.0046 mole) dissolved in 20 ml of methanol. After 3.5 hours, another 0.3 g (0.00048 mole) of MMPP is added in 1 ml of methanol. It is left to react at ambient temperature overnight. 50 ml of water, 5 ml of a saturated NaHCO 3 solution are added and the mixture is extracted with ethyl acetate. The solvent is evaporated off and the title product is obtained. Mp: 142-145 ° C.

    EXEMPLE 66EXAMPLE 66 4-benzyloxy-3-méthylsulfonyl-phénol4-benzyloxy-3-methylsulfonyl-phenol

    On dissout 3,09 g (0,008 mole) du produit de l'exemple 65 dans 40 ml de THF et on ajoute 10,5 ml de NaOH 1N (0,010 mole). Après 4 heures on ajoute 25 ml d'eau et du NaH2PO4 jusqu'à pH 7 et on extrait à l'acétate d'éthyle. On lave avec des solutions aqueuses de NaHCO3 et de NaCl et on évapore le solvant. On obtient le produit du titre. P.f : 154-156°C.3.09 g (0.008 mole) of the product of Example 65 are dissolved in 40 ml of THF and 10.5 ml of 1N NaOH (0.010 mole) are added. After 4 hours, 25 ml of water and NaH 2 PO 4 are added to pH 7 and the mixture is extracted with ethyl acetate. Wash with aqueous NaHCO 3 and NaCl solutions and the solvent is evaporated. The title product is obtained. Mp: 154-156 ° C.

    EXEMPLE 67EXAMPLE 67 4-benzyloxy-3-méthylsulfonyl-1-(2,3-époxypropoxy)-benzène.4-benzyloxy-3-methylsulfonyl-1- (2,3-epoxypropoxy) benzene.

    On laisse sous agitation pendant 10 minutes 0,158 g (0,00395) de NaOH dans 10 ml de DMF et on ajoute 1 g (0,00359 mole) du phénol obtenu dans l'exemple 66. Après 10 minutes on ajoute 0,977 g (0,00377 mole) de glycidylnosilate dans 5 ml de DMF et on laisse réagir pour 24 heures à température ambiante. On ajoute 100 ml d'eau et 2 ml d'une solution de NaH2PO4 on extrait à l'acétate d'éthyle et on lave à l'eau. Le brut de réaction est purifié par chromathographie en éluant par un mélange CH2Cl2/acétate d'éthyle = 98/2 ensuite 97/3 et 96/4. On obtient le produit du titre. P.f. : 78-82°C. 0.158 g (0.00395) of NaOH in 10 ml of DMF is left stirring for 10 minutes and 1 g (0.00359 mole) of the phenol obtained in Example 66 is added. After 10 minutes, 0.977 g (0 , 00377 mol) of glycidylnosilate in 5 ml of DMF and allowed to react for 24 hours at room temperature. 100 ml of water and 2 ml of a solution of NaH 2 PO 4 are added, the mixture is extracted with ethyl acetate and washed with water. The crude reaction product is purified by chromathography, eluting with a CH 2 Cl 2 / ethyl acetate mixture = 98/2 then 97/3 and 96/4. The title product is obtained. Mp: 78-82 ° C.

    EXEMPLE 68EXAMPLE 68 68a) 3-[1-(5-éthoxycarbonylpyrid-2-yl)-4-pipéridinamino]-1-[(4-benzyloxy-3-méthylsulfonyl)-phénoxy]-2-propanol 68a) 3- [1- (5-ethoxycarbonylpyrid-2-yl) -4-piperidinamino] -1 - [(4-benzyloxy-3-methylsulfonyl) -phenoxy] -2-propanol

    On chauffe au reflux pendant 6 heures 0,700 g (0.00209 mole) du produit de l'exemple 67 et 0,574 g (0,0023 mole) du produit de l'exemple 4 sous forme de base dans 6 ml d'éthanol. On évapore le solvant, on ajoute à l'huile ainsi formé de l'acétate d'éthyle et on laisse cristalliser le produit. On obtient le produit du titre. P.f. : 111-114°C0.700 g (0.00209 mole) of the product is heated at reflux for 6 hours. Example 67 and 0.574 g (0.0023 mole) of the product of Example 4 in the form of the base in 6 ml of ethanol. The solvent is evaporated, acetate is added to the oil thus formed ethyl and allowed to crystallize the product. The title product is obtained. Mp : 111-114 ° C

    68b) 3-[1-(5-éthoxycarbonylpyrid-2-yl)-4-pipéridinamino]-1-[(4-hydroxy-3-méthylsulfonyl)-phénoxy]-2-propanol 68b) 3- [1- (5-ethoxycarbonylpyrid-2-yl) -4-piperidinamino] -1 - [(4-hydroxy-3-methylsulfonyl) -phenoxy] -2-propanol

    Le produit issu de l'étape précédante est traité avec CF3COOH selon le procédé décrit dans l'exemple 26b, le produit brut étant purifié par flash-chromatographie en élunat par un mélange CH2Cl2/MeOH/NH3 conc. = 90/10/1. On obtient le produit du titre.The product resulting from the preceding stage is treated with CF 3 COOH according to the process described in example 26b, the crude product being purified by flash-chromatography in elunate by a mixture CH 2 Cl 2 / MeOH / NH 3 conc. = 90/10/1. The title product is obtained.

    EXEMPLEEXAMPLE 6969 3-[1-(6-chloro-pyrid-2yl)-4-pipéridinylamino]-1-[-4-hydroxy-3-méthansulfonamido)-phenoxy]-2-propanol3- [1- (6-chloro-pyrid-2-yl) -4-piperidinylamino] -1 - [- 4-hydroxy-3-méthansulfonamido) -phenoxy] -2-propanol

    On fait réagir le produit de l'exemple 50 avec la 4-amino-1-(6-chloropyrid-2yl)-pipéridine (préparée comme décrit dans EP 21973) selon le procédé décrit dans l'exemple 51.The product of Example 50 is reacted with 4-amino-1- (6-chloropyrid-2yl) -piperidine (prepared as described in EP 21973) according to the method described in Example 51.

    On obtient le produit du titre.The title product is obtained.

    EXEMPLE 70EXAMPLE 70 3-[1-(6-éthoxycarbonylpyrid-2yl)-4-pipéridinylamino]-1-[-4-hydroxy-3-méthansulfonamido)-phenoxy]-2-propanol3- [1- (6-éthoxycarbonylpyrid-2yl) -4-piperidinylamino] -1 - [- 4-hydroxy-3-méthansulfonamido) -phenoxy] -2-propanol

    On fait réagir le produit de l'exemple 50 avec le produit de l'exemple 57 (base) dans les conditions décrites dans l'exemple 51. On obtient le produit du titre.The product of Example 50 is reacted with the product of Example 57 (base) under the conditions described in Example 51. The title product is obtained.

    EXEMPLE 71EXAMPLE 71 3-[1-(6-chloropyrid-2-yl)-4-pipéridinylamino]-1-(4-hydroxyphénoxy)-2-propanol3- [1- (6-chloropyrid-2-yl) -4-piperidinylamino] -1- (4-hydroxyphenoxy) -2-propanol

    En opérant comme décrit dans l'exemple 58 mais en utilisant la 4-amino-1-(6-chloropyrid-2yl)-pipéridine en lieu du produit de l'exemple 57 on obtient le produit du titre.By operating as described in Example 58 but using 4-amino-1- (6-chloropyrid-2yl) -piperidine instead of the product of example 57 we obtain the product of title.

    Claims (10)

    1. Compounds of formula (Ia) :
      Figure 00330001
      in which
      R1a
      represents hydrogen, an -S(O)2-(C1-C6)Alk group, a -CO(C1-C4)Alk group, an -NHSO2- (C1-C4)Alk group, an NHCO(C1-C4)Alk group, a 2-furyl group or a halogen;
      R2
      represents hydrogen or a (C1-C4)Alk group, a (C1-C4)alkoxy group, a halogen, -COOH, -COO(C1-C4)Alk, -CN, -CONR3R4, -NO2, -SO2NH2 or -NHSO2(C1-C4)Alk;
      m and n
      are independently 0, 1 or 2;
      R3 and R4
      independently represent hydrogen or a (C1-C4)Alk group;
      Z
      is 1 or 2;
      and their salts or solvates.
    2. Compounds according to Claim 1, of formula:
      Figure 00340001
      where
      R1
      represents hydrogen, an -S(O)2-(C1-C4)Alk group, a -CO(C1-C4)Alk group or an -NHSO2- (C1-C4)Alk group;
      R2
      represents hydrogen or a (C1-C4)Alk group, a (C1-C4)alkoxy group, a halogen, -COOH, -COO(C1-C4)Alk, -CN, -CONR3R4, -NO2, -SO2NH2 or -NHSO2(C1-C4)Alk;
      m and n
      are independently 0, 1 or 2;
      R3 and R4
      independently represent hydrogen or a (C1-C4)Alk group;
      Z
      is 1 or 2;
      and their salts or solvates.
    3. Compounds according to Claim 1 or 2, where R2 is in the 5 or 6 position of the pyridine.
    4. Compounds according to Claim 1 or 2, where n and m are zero.
    5. Compounds according to Claim 1 or 2, where the (C1-C4)Alk group is a methyl or ethyl group.
    6. Compounds according to Claim 1 or 2, where R2 is chosen from -COOH, -COO(C1-C4)Alk, -CN, -NO2, -CONR2R3 and -NHSO2-(C1-C4)Alk.
    7. Compounds according to Claim 1 or 2, where R2 is a halogen.
    8. Process for the preparation of the compounds of formulae (Ia) and (I) of Claims 1 and 2, characterized in that a compound of formula (II)
      Figure 00350001
      in which R1b is R1a or R1 as indicated in Claim 1 or 2, P' is a protective group and X is a group of formula (a) or (b),
      Figure 00350002
      where Gp is a leaving group, is reacted with an amine of formula (III)
      Figure 00350003
      in which n, m and R2 are as indicated in Claim 1, the group P' being cleaved and the compound of formula (Ia) or (I) thus obtained optionally being converted into one of its salts.
    9. Pharmaceutical composition comprising, as active principle, a compound of formula (Ia) or (I) according to Claims 1 to 7 or one of its pharmaceutically acceptable salts.
    10. Use of a compound of formula (Ia) or (I) according to Claims 1 to 7 or one of its pharmaceutically acceptable salts for the preparation of medicaments indicated in irritable bowel syndrome, or with a modulating effect on intestinal motricity or with a lipolytic, antiobesity, antidiabetic, psychotropic, antiglaucomatous, cicatrizant or antidepressant effect, as inhibitor of uterine contractions, as tocolytics for preventing or delaying premature labour, or for the treatment and/or prophylaxis of dysmenorrhoea.
    EP99923710A 1998-06-18 1999-06-10 Phenoxylpropanolamines, method for the production thereof and pharmaceutical compositions containing the same Expired - Lifetime EP1087961B1 (en)

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    CO5011052A1 (en) 2001-02-28
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    US6649627B1 (en) 2003-11-18
    FR2780057B1 (en) 2002-09-13
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